CN111448193B

CN111448193B - SRPK1 inhibitors

Info

Publication number: CN111448193B
Application number: CN201880075104.5A
Authority: CN
Inventors: 安德鲁·道格拉斯·巴克斯特; J·莫里斯; 安德鲁·大卫·莫利
Original assignee: Exonate Ltd
Current assignee: Exonate Ltd
Priority date: 2017-09-27
Filing date: 2018-09-26
Publication date: 2023-12-22
Anticipated expiration: 2038-09-26
Also published as: CA3077749A1; AU2018341084A1; US11420969B2; EP3687990A1; US20200270249A1; JP2020535172A; US20220389015A1; JP7261793B2; AU2018341084B2; WO2019063996A1; CN111448193A

Abstract

Described herein are methods of anti-angiogenic therapy, e.g., treatment of ocular neovascularization or treatment of cancer, treatment of hyperpermeable disorders, treatment of neurological and neurodegenerative disorders, treatment of pain, treatment or prevention of fibrosis, and compounds useful in such methods.

Description

SRPK1 inhibitors

Technical Field

The present invention relates to anti-angiogenic therapies and compounds useful in anti-angiogenic therapies, in particular, the invention relates to the treatment of conditions characterized by neovascularization (e.g., ocular neovascularization, particularly age-related macular degeneration and macular edema) and compounds useful in the treatment of such conditions.

The invention also relates to the treatment of neoplasia, e.g., cancer, and compounds useful for treating cancer.

The invention also relates to the treatment of hyperpermeable disorders and to compounds useful in the treatment of hyperpermeable disorders.

The invention also relates to the treatment of and compounds for the treatment of neurological and neurodegenerative disorders (e.g., alzheimer's disease).

The invention also relates to the treatment of pain and compounds for use in the treatment of pain.

The invention also relates to methods for reducing the risk of preeclampsia and compounds for use in these methods.

Background

Age-related macular degeneration (AMD), a disease that causes vision loss that affects the central area of the macula, is a major cause of blindness in people over 50 years of age. Exudative AMD is the most severe form of AMD, which is mainly caused by the choroidal circulation under the macula and is characterized by Choroidal Neovascularization (CNV). CNV is the abnormal growth of new blood vessels from the choroid to the Retinal Pigment Epithelium (RPE), which is thought to cause visual loss due to leakage of blood and serum under the RPE, such leakage ultimately leading to photoreceptor loss, retinal detachment, and dense macular scarring. Vascular Endothelial Growth Factor (VEGF) is a key factor in angiogenesis and vascular leakage, which is upregulated during the development of CNV and has become a critical therapeutic target for the treatment of exudative AMD.

Macular edema is produced when abnormal leakage and fluid accumulation occurs in the macula from damaged blood vessels near the retina. A common cause of macular edema is diabetic retinopathy, but macular edema can also occur after ocular surgery, associated with age-related macular degeneration or due to inflammatory diseases affecting the eye. Any disease that damages blood vessels in the retina may lead to macular edema. Like AMD, VEGF is upregulated during progression of the disease AMD and therefore it is an attractive target.

VEGF is a complex gene that alternatively splices to form a family of multiple isoforms, each of which differs in biological properties, activity, and function. Most cells normally express the isoform VEGF ₁₂₁ ，VEGF ₁₆₅ And VEGF (vascular endothelial growth factor) ₁₈₉ While VEGF ₁₄₅ And VEGF (vascular endothelial growth factor) ₂₀₆ Is relatively rare. Most VEGF isoforms (VEGF ₁₁₁ Except) comprise exons 1-5, except for the different parts of exons 6 and 7 encoding the Heparin Sulfate (HS) binding domain. The alteration in the use of these exons results in alteration of the biological properties of the alternatively spliced isoforms, e.g., the ability to bind cell surface heparan sulfate proteoglycans and release angiogenic factors.

In 2002, 66 bases downstream from the Proximal Splice Site (PSS) to the Distal Splice Site (DSS) showed differential splicing of the eighth exon. Alternative splicing in this region produces a second family isoform (VEGF _xxx b) Of note are their anti-angiogenic properties. WO03/102105 (the entire contents of which are incorporated herein by reference) discloses alternatively spliced isoforms and their therapeutic significance.

During pathological angiogenesis, pro-angiogenic isoforms are selectively upregulated, suggesting VEGF _xxx And VEGF (vascular endothelial growth factor) _xxx b may have respective regulatory pathways. These anti-angiogenic isoforms (e.g., VEGF ₁₆₅ b and VEGF ₁₂₁ b) Has been shown to be effective against angiogenesis after intraocular injection in animal models of retinal and choroidal neovascularization, and to produce cytoprotective effects of endothelial cells and retinal epithelial cells.

The first FDA approved therapy for the treatment of neovascular AMD was VEGF, month 12 2004 ₁₆₅ ，VEGF ₁₈₉ And VEGF (vascular endothelial growth factor) ₂₀₆ Specific aptamer, sodium pipadatinib(Pegaptanib Sodium (Macugen)). During clinical trials, pipadatinib reduced the risk of severe vision loss and slowed the progression of neovascular AMD in a dose-dependent manner, but failed to produce significant improvement in vision. In 2006, FDA approved ranibizumab (Ranibizumab (Lucentis), a novel humanized anti-VEGF antibody fragment) for the treatment of neovascular AMD. FDA approval for ranibizumab is based on three clinical trial results: approximately 95% of patients treated with Lucentis (0.5 mg) maintain visual acuity (defined as a decrease of less than 15 letters) monthly and less than 40% of patients after one year of treatment produce vision improvement (defined as an increase of 15 letters or more) compared to 11% of patients in the sham-treated control group. However, current treatment regimens require once a month administration of Lucentis by intraocular injection, which not only causes discomfort to the patient, but also leads to increased intraocular pressure and creates a risk of (although small) endophthalmitis and other serious side effects. Furthermore, bevacizumab (Avastin), an anti-VEGF antibody derived from Lucentis, has been shown to bind VEGF with the same potency ₁₆₅ b and VEGF ₁₆₅ Thus, bevacizumab targets pro-angiogenic VEGF isoforms and anti-angiogenic VEGF isoforms.

Since both the anti-angiogenic and angiogenic isoforms of VEGF are derived from the same gene, control of the isoform family is a result of control of alternative splicing. Several pathways have been identified to control the splicing of VEGF at the proximal splice site, involving the RNA binding protein SRSF1 and its kinase SRPK1, which are key requirements for cell-dependent use of the proximal splice site and thus produce pro-angiogenic isoforms of VEGF. The knockout of SRPK1 effectively reduced VEGF-mediated in vivo angiogenesis in tumors and inhibition of SRPK1 and SRPK2 reduced in vivo angiogenesis.

WO2005/063293 discloses a class of SRPK inhibitors comprising SRPIN340 and derivatives and analogues thereof. WO2014/060763, WO 2015/159203 and WO2017/064512 disclose SRPK inhibitors targeting SRPK1, particularly as anti-angiogenic agents, neuroprotective agents, agents for the treatment or prevention of hyperpermeability disorders, as agents for the treatment of pain, as agents for reducing the risk of pre-eclampsia or for the treatment of pre-eclampsia.

The present invention is based, in part, on novel small molecule inhibitors of targeted SRPK1, which are particularly useful as anti-angiogenic agents, neuroprotective agents, agents for the treatment or prevention of hyperpermeability disorders, as agents for the treatment of pain, and agents for reducing the risk of or treating preeclampsia.

Modern medical treatment regimens increasingly combine several drugs. Most of the drugs conventionally used are metabolized by cytochrome P450 (CYP) enzymes. Moreover, most of these enzymes are polymorphic, in particular CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Patients that overexpress these enzymes are referred to as "fast metabolizers" and those that are under-expressed for these enzymes are referred to as "slow metabolizers". Drugs that inhibit these enzymes may cause drug-drug interactions that may lead to toxic exposure of other drugs used in combination.

The present invention is also based on at least the following unexpected findings: these low molecular weight compounds do not exhibit any CYP inhibition associated with previously known SRPK1 inhibitors.

Thus, the compounds of the present invention will have broader therapeutic applications than the previously described SRPK1 inhibitors.

Disclosure of Invention

In a first aspect, the present invention provides a compound of the following general formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, for use in the treatment or prevention of ocular neovascularization:

wherein:

n=1, 2 or 3;

R ₁ is halogen, difluoromethyl, trifluoromethyl, cyclopropyl, methyl, methoxy or trifluoromethoxy;

R ₂ is furyl group, anyOptionally having a 4-tetrahydropyranyl or 4-pyridinyl substituent, or a 2-pyridinyl group;

R ₃ is hydroxy, hydroxymethyl, methoxy, C ₁ -C ₃ Alkyl, carboxyl, -C (O) NR ₅ R ₆ Or CH (CH) ₂ NR ₅ R ₆ ；

R ₄ Hydrogen, methyl, ethyl, cyclopropyl, phenyl, benzyl or cyclopropylmethyl; or alternatively

R ₃ And R is ₄ Forms a carbocyclic or heterocyclic ring together with the carbon atoms adjacent thereto; and is also provided with

R ₅ And R is ₆ Independently selected from: hydrogen, methyl, ethyl or propyl; or alternatively

R ₅ And R is ₆ Are linked together to form a nitrogen-containing heterocycle.

The term "ocular neovascularization" includes within its scope diseases and disorders characterized by ocular neovascularization, which include, for example: choroidal neovascularization, such as age-related macular degeneration. The term "ocular neovascularization" also includes within its scope diseases and disorders characterized by retinal neovascularization. For example, the term "ocular neovascularization" also includes within its scope diseases and conditions such as macular edema, for example, diabetic macular edema that may result from diabetic retinopathy (a complication of diabetes).

In a second aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, for use in the topical treatment or prophylaxis of ocular neovascularisation.

The first and second aspects of the invention also provide methods of treating or preventing ocular neovascularization by administering a compound of formula (I) to a subject in need of such treatment, respectively, and the use of a compound of formula (I) in the manufacture of a medicament for treating or preventing ocular neovascularization (e.g., for dose-dependent and/or topical treatment).

Surprisingly and unexpectedly, the compounds used in the present invention are capable of treating or preventing or locally treating or preventing ocular neovascularization in a dose dependent manner, relative to the prior art. Dose-dependent therapies are not inherently predictable, but are highly desirable and beneficial for effective treatment.

The evaluation of the inhibitory effect of new chemical groups on CYP is critical in determining its suitability as a drug. CYP enzymes (a family of cytochrome P450 enzymes, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A 4) are the primary sites of drug metabolism and other exogenous agent metabolism. Effective inhibition of any CYP enzyme by a candidate drug may result in accumulation of the drug to toxic levels and adverse drug-drug interactions (DDI) in the subject, wherein metabolism of the other drug used in combination is impaired or prevented, resulting in higher than expected exposure and toxicity problems of the drug used in combination.

It can be seen from table 3 that although the prior art compounds disclosed in WO 2015/159203 and WO2017/064512 are potent SRPK1 inhibitors, they are also affected by potent inhibitors of at least CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes and therefore they are not suitable for systemic administration. Surprisingly and unexpectedly, the compounds of the present invention do not exhibit the CYP inhibition problem of any prior art compounds, while still being potent SRPK1 inhibitors, relative to the prior art.

Specific compounds of the general formula (I) and preferred or exemplary subclasses of compounds of the general formula (I) may be specifically mentioned for use in the present invention.

In order to avoid confusion as to whether a particular object is to be confused,refers to alkyl bridging units located between adjacent carbon atoms. Thus, the above group is a methylene bridge (CH) where n=1 ₂ ) The method comprises the steps of carrying out a first treatment on the surface of the Ethylene bridge (CH) where n=2 ₂ CH ₂ ) The method comprises the steps of carrying out a first treatment on the surface of the And a propylene bridge (CH) in which n=3 ₂ CH ₂ CH ₂ )。

The compounds of formula (I) and pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof are novel and as compounds per se (and their use in the treatment or prevention of ocular neovascularisation) which constitute further aspects of the invention.

Pharmaceutical compositions comprising the novel compounds and the use of the novel compounds and pharmaceutical compositions comprising the novel compounds in anti-angiogenic therapy, including the treatment and prevention of disorders and diseases characterized by abnormal or excessive angiogenesis, the treatment of hyperpermeable disorders, the treatment of neurological and neurodegenerative disorders, the treatment of non-inflammatory pain and the methods of reducing the risk of preeclampsia described herein constitute further aspects of the invention.

Accordingly, the present invention also provides (i) a method of treating or preventing a disease or disorder characterized by abnormal or excessive angiogenesis as described herein; (ii) Methods of treating or preventing a hyperpermeability disorder described herein; (iii) Methods of treating or preventing neurological and neurodegenerative disorders described herein; (iv) a method of treating or preventing pain; and (v) a method of reducing the risk of preeclampsia, the method comprising administering to a patient in need thereof a compound of formula (I).

In some examples, the compound of formula (I) may be a compound wherein R ₃ Is C ₁ -C ₃ Alkyl (i.e., selected from methyl, ethyl and propyl).

In some examples, the compound of formula (I) may be a compound wherein:

R ₃ is hydroxy, hydroxymethyl, methoxy, methyl or carboxyl; and is also provided with

R ₄ Is methyl, ethyl, cyclopropyl, phenyl, benzyl or cyclopropylmethyl.

In some examples, the compound of formula (I) may be a compound wherein R ₃ Is hydroxy, and R ₄ Is methyl, ethyl, cyclopropyl, phenyl, benzyl or cyclopropylmethyl.

In some examples, the compound of formula (I) may be a compound wherein:

R ₃ is-C (O) NR ₅ R ₆ Or CH (CH) ₂ NR ₅ R ₆ ；

R ₄ Is hydrogen, methyl, ethylA group, cyclopropyl, phenyl, benzyl or cyclopropylmethyl; and is also provided with

R ₅ And R is ₆ Independently selected from hydrogen, methyl, ethyl or propyl; or alternatively

In some examples, the compound of formula (I) may be a compound wherein n=1 or 3, and wherein the compound is enantiomerically pure.

In some examples, the compound of formula (I) may be a compound wherein:

n=1 or 3;

R ₃ is hydroxy, -C (O) NR ₅ R ₆ Or CH (CH) ₂ NR ₅ R ₆ ；

R ₄ Is hydrogen or methyl;

R ₅ and R is ₆ Independently selected from hydrogen and methyl; or alternatively

R ₅ And R is ₆ Are linked together to form a nitrogen-containing heterocycle; and is also provided with

Wherein the compound is the R enantiomer or the S enantiomer.

In some examples, the compound of formula (I) may be a compound wherein R ₁ Is chloro, difluoromethyl, trifluoromethyl, cyclopropyl, methyl, methoxy or trifluoromethoxy (e.g., chloro, trifluoromethyl or cyclopropyl).

In some examples, the compound of formula (I) may be a compound of formula (II) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof,

wherein:

n=1, 2 or 3;

R ₂ Is 4-tetrahydropyranyl or 4-pyridinyl;

R ₄ Hydrogen, methyl, ethyl, cyclopropyl, phenyl, benzyl or cyclopropylmethyl; and is also provided with

In some examples, the compound of formula (I) may be a compound of formula (IIa) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof:

wherein:

R ₂ is 4-tetrahydropyranyl or 4-pyridinyl;

In some examples, the compound of formula (I) may be a compound of formula (IIb) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof:

wherein:

R ₂ Is 4-tetrahydropyranyl or 4-pyridinyl;

In some examples, the compound of formula (I) may be a compound of formula (IIc) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof:

wherein:

R ₂ is 4-tetrahydropyranyl or 4-pyridinyl;

In some examples, the compound of formula (II), (IIa), (IIb) or (IIc) may be a compound wherein R ₃ Is C ₁ -C ₃ Alkyl (i.e., selected from the group consisting of methyl, ethyl, and propyl).

In some examples, the compound of formula (II), (IIa), (IIb) or (IIc) may be a compound wherein:

R ₃ Is hydroxy, hydroxymethyl, methoxy, methyl, carboxy, -C (O) NR ₅ R ₆ Or CH (CH) ₂ NR ₅ R ₆ ；

R ₄ Methyl, ethyl, cyclopropyl, phenyl, benzyl or cyclopropylmethyl; and is also provided with

In some examples, the compound of formula (II), (IIa), (IIb) or (IIc) may be a compound wherein R ₃ Is a hydroxyl group; and R is ₄ Is methyl, ethyl, cyclopropyl, phenyl, benzyl or cyclopropylmethyl.

R ₃ is-C (O) NR ₅ R ₆ Or CH (CH) ₂ NR ₅ R ₆ ；

R ₅ And R is ₆ Are linked together to form a nitrogen-containing heterocycle (e.g., a 5-or 6-membered nitrogen-containing heterocycle, e.g., a 5-or 6-membered unsaturated heterocycle).

In some examples, the compound of formula (II), (IIa), (IIb) or (IIc) may be a compound wherein R ₃ is-C(O)NR ₅ R ₆ Or CH (CH) ₂ NR ₅ R ₆ The method comprises the steps of carrying out a first treatment on the surface of the And R is ₅ And R is ₆ Are linked together to form a nitrogen-containing heterocycle; and wherein the nitrogen-containing heterocycle is a pyrrolidine, piperidine or morpholine heterocycle.

In some examples, the compound of formula (II), (IIa), (IIb), or (IIc) may be a compound wherein n=1 or 3, and the compound is enantiomerically pure.

n=1 or 3;

R ₃ is hydroxy, -C (O) NR ₅ R ₆ Or CH (CH) ₂ NR ₅ R ₆ ；

R ₄ Is hydrogen or methyl;

Wherein the compound is the R enantiomer or the S enantiomer.

In some examples, the compound of formula (II), (IIa), (IIb) or (IIc) may be a compound wherein R ₁ Is chloro, difluoromethyl, trifluoromethyl, cyclopropyl, methyl, methoxy or trifluoromethoxy (e.g., chloro, trifluoromethyl or cyclopropyl).

In some examples, the compound of formula (I) may be a compound of formula (III) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof:

wherein:

n=1, 2 or 3;

R ₂ is hydroxy, hydroxymethyl, methoxy, C ₁ -C ₃ Alkyl, carboxyl, -C (O) NR ₄ R ₅ Or CH (CH) ₂ NR ₄ R ₅ ；

R ₃ Hydrogen, methyl, ethyl, cyclopropyl, phenyl, benzyl or cyclopropylmethyl; and is also provided with

R ₄ And R is ₅ Independently selected from: hydrogen, methyl, ethyl or propyl; or alternatively

R ₄ And R is ₅ Are linked together to form a nitrogen-containing heterocycle.

In some examples, the compound of formula (I) may be a compound of formula (IIIa) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof:

wherein:

In some examples, the compound of formula (I) may be a compound of formula (IIIb) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof:

wherein:

In some examples, the compound of formula (I) may be a compound of formula (IIIc) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof:

wherein:

In some examples, the compound of formula (III), (IIIa), (IIIb) or (IIIc) may be a compound wherein R ₃ Is C ₁ -C ₃ Alkyl (i.e., selected from the group consisting of methyl, ethyl, and propyl).

In some examples, the compound of formula (III), (IIIa), (IIIb) or (IIIc) may be a compound wherein:

R ₂ is hydroxy, hydroxymethyl, methoxy, methyl or carboxyl; and is also provided with

R ₃ Is methyl, ethyl, cyclopropyl, phenyl, benzyl or cyclopropylmethyl.

In some examples, the compound of formula (III), (IIIa), (IIIb) or (IIIc) may be a compound wherein R ₂ Is a hydroxyl group; and R is ₃ Is methyl, ethyl, cyclopropyl, phenyl, benzyl or cyclopropylmethyl.

R ₂ is-C (O) NR ₄ R ₅ Or CH (CH) ₂ NR ₄ R ₅ ；

R ₃ Methyl, ethyl, cyclopropyl, phenyl, benzyl or cyclopropylmethyl; and is also provided with

R ₄ And R is ₅ Independently selected from hydrogen and methyl; or alternatively

R ₄ And R is ₅ Are linked together to form a nitrogen-containing heterocycle (e.g., a 5-or 6-membered nitrogen-containing heterocycle, e.g., a 5-or 6-membered unsaturated heterocycle).

R ₃ is-C (O) NR ₅ R ₆ Or CH (CH) ₂ NR ₅ R ₆ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

R ₅ And R is ₆ And linked together to form a nitrogen-containing heterocycle, wherein the nitrogen-containing heterocycle is a pyrrolidine, piperidine or morpholine heterocycle.

In some examples, the compound of formula (III), (IIIa), (IIIb) or (IIIc) may be a compound wherein: n=1 or 3, and the compounds are enantiomerically pure.

n=1 or 3;

R ₂ is hydroxy, -C (O) NR ₄ R ₅ Or CH (CH) ₂ NR ₄ R ₅ ；

R ₃ Is hydrogen or methyl;

R ₄ And R is ₅ Are linked together to form a nitrogen-containing heterocycle; and is also provided with

Wherein the compound is the R enantiomer or the S enantiomer.

In some examples, the compound of formula (III), (IIIa), (IIIb) or (IIIc) may be a compound wherein: r is R ₁ Is chloro, difluoromethyl, trifluoromethyl, cyclopropyl, methyl, methoxy or trifluoromethoxy (e.g., chloro, trifluoromethyl or cyclopropyl).

In some examples, the compound of formula (I), (II), (IIa), (IIb), or (IIc) may be a compound wherein: r is R ₁ And R is ₂ Is as defined above, and R ₃ And R is ₄ Together with adjacent methylene groups (i.e., ring carbon atoms) form a carbocyclic or heterocyclic ring (e.g., a 3-to 6-membered carbocyclic ring or a 3-to 6-membered heterocyclic ring), thereby forming a spiro compound. The carbocycle or heterocycle (e.g., 3-to 6-membered carbocycle or 3-to 6-membered heterocycle) may be an aromatic or non-aromatic carbocycle or heterocycle. The heterocyclic ring may include one or more heteroatoms selected from O, N or S. For example, disclosed herein are compounds wherein the carbocycle or heterocycle is a 5-or 6-membered carbocycle or heterocycle, each of which may have a substituent, especially a non-aromatic 5-or 6-membered carbocycle or heterocycle, which may each have a substituent. In some examples, the 5-or 6-membered heterocyclic ring comprises one carbon atom. In some examples, the 5-or 6-membered heterocyclic ring comprises one carbon atom and another heteroatom selected from O, N and S. Specific examples of 5-or 6-membered carbocycles include cyclopentyl, cyclopentadienyl, cyclohexyl, and phenyl. Specific examples of 5-or 6-membered heterocycles include pyrrolidinyl, piperidinyl, Morpholinyl, piperazinyl, which may each have one or more substituents. In some examples, the 5-or 6-membered carbocyclic or heterocyclic ring comprises a member selected from the group consisting of: c (C) _1-6 Alkyl, halogen, hydroxy, C _1-6 Alkoxy, oxygen, cyano, amino substituents.

In some examples, the compound of formula (III), (IIIa), (IIIb) or (IIIc) may be a compound wherein: r is R ₁ Is as defined above and R ₂ And R is ₃ Together with adjacent methylene groups (i.e., ring carbon atoms) form a carbocyclic or heterocyclic ring (e.g., a 3-to 6-membered carbocyclic ring or a 3-to 6-membered heterocyclic ring), thereby forming a spiro compound. The carbocycle or heterocycle (e.g., 3-to 6-membered carbocycle or 3-to 6-membered heterocycle) may be an aromatic carbocycle or heterocycle or a non-aromatic carbocycle or heterocycle. The heterocyclic ring may comprise one or more heteroatoms selected from O, N or S. For example, disclosed herein are the following compounds, wherein: the carbocycle or heterocycle is a 5-or 6-membered carbocycle or heterocycle, and each of the 5-or 6-membered carbocycle or heterocycle may have a substituent, particularly a non-aromatic 5-or 6-membered carbocycle or heterocycle, which may have a substituent. In some examples, the 5-or 6-membered heterocyclic ring comprises one nitrogen atom. In some examples, the 5-or 6-membered heterocyclic ring comprises one nitrogen atom and one other heteroatom selected from O, N and S. Specific examples of 5-or 6-membered carbocycles include: cyclopentyl, cyclopentadienyl, cyclohexyl, and phenyl. Specific examples of 5-or 6-membered heterocycles include: pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, which may each have one or more substituents. In some examples, the 5-or 6-membered carbocyclic or heterocyclic ring comprises a member selected from C _1-6 Alkyl, halogen, hydroxy, C _1-6 Alkoxy, oxygen, cyano, amino substituents.

In some examples, the compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc) may be a compound wherein: r is R ₁ Is halogen (selected from fluorine, chlorine, bromine and iodine). In some examples, the compound of formula (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), or (IIIc) may be a compound wherein: r is R ₁ Is chlorine.

In some casesIn examples, compounds of formula (I) are IC for CYP1A2 ₅₀ May be at least 5 μm, such as at least 6 μm, such as at least 7 μm, such as at least 8 μm, such as at least 9 μm, such as at least 10 μm, such as at least 15 μm, such as at least 20 μm, such as at least 25 μm, such as about 30 μm.

In some examples, the compound of formula (I) is an IC for CYP2C9 ₅₀ May be at least 5 μm, such as at least 6 μm, such as at least 7 μm, such as at least 8 μm, such as at least 9 μm, such as at least 10 μm, such as at least 15 μm, such as at least 20 μm, such as at least 25 μm, such as about 30 μm.

In some examples, the compound of formula (I) is an IC for CYP2C19 ₅₀ May be at least 5 μm, such as at least 6 μm, such as at least 7 μm, such as at least 8 μm, such as at least 9 μm, such as at least 10 μm, such as at least 15 μm, such as at least 20 μm, such as at least 25 μm, such as about 30 μm.

In some examples, the compound of formula (I) is IC to CYP2D6 ₅₀ May be at least 5 μm, such as at least 6 μm, such as at least 7 μm, such as at least 8 μm, such as at least 9 μm, such as at least 10 μm, such as at least 15 μm, such as at least 20 μm, such as at least 25 μm, such as about 30 μm.

In some examples, the compound of formula (I) is an IC for CYP3A4 ₅₀ May be at least 5 μm, such as at least 6 μm, such as at least 7 μm, such as at least 8 μm, such as at least 9 μm, such as at least 10 μm, such as at least 15 μm, such as at least 20 μm, such as at least 25 μm, such as about 30 μm.

In some examples, the compound of formula (I) may be a compound of table 2. Specifically disclosed compounds of formula (I) include:

n- (2- (4-hydroxy-4-methylpiperidin-1-yl) -5- (trifluoromethyl) phenyl) pyridine carboxamide;

n- (5-chloro-2- (4-hydroxy-4-methylpiperidin-1-yl) -phenyl) pyridine carboxamide;

n- (5-cyclopropyl-2- (4-hydroxy-4-methylpiperidin-1-yl) phenyl) -pyridinecarboxamide;

n- (2- (4-hydroxy-4-methylpiperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

n- (5-chloro-2- (4-hydroxy-4-methylpiperidin-1-yl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

N- (5-cyclopropyl-2- (4-hydroxy-4-methylpiperidin-1-yl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

n- (5- (difluoromethyl) -2- (4-hydroxy-4-methyl-piperidin-1-yl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

n- (2- (4-hydroxy-4-methylpiperidin-1-yl) -5-methylphenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

n- (2- (4-hydroxy-4-methylpiperidin-1-yl) -5-methoxyphenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

n- (2- (4-hydroxy-4-methylpiperidin-1-yl) -5- (trifluoromethoxy) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

n- (2- (4-hydroxy-4-methylpiperidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4-hydroxy-4-methylpiperidin-1-yl) -5-methylphenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (5- (difluoromethyl) -2- (4-hydroxy-4-methyl-piperidin-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4-hydroxy-4-methylpiperidin-1-yl) -5-methoxyphenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4-hydroxy-4-methylpiperidin-1-yl) -5- (trifluoromethoxy) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

N- (5-cyclopropyl-2- (4-hydroxy-4-methylpiperidin-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4-methoxy-4-methylpiperidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4-hydroxy-4-methylazepan-1-yl) -5- (trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

n- (2- (4-ethyl-4-hydroxypiperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4-cyclopropyl-4-hydroxypiperidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4-hydroxy-4-phenylpiperidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4- (cyclopropylmethyl) -4-hydroxypiperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4- (hydroxymethyl) -4-methylpiperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

n- (2- (4- (hydroxymethyl) -4-methylpiperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

4-methyl-1- (2- (5- (pyridin-4-yl) furan-2-carboxamido) -4- (trifluoromethyl) phenyl) -piperidine-4-carboxylic acid;

4-methyl-1- (2- (5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamido) -4- (trifluoromethyl) phenyl) -piperidine-4-carboxylic acid;

n- (2- (4, 4-dimethylpiperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

n- (2- (4, 4-dimethylpiperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

1- (2- (picolinamido) -4- (trifluoromethyl) phenyl) -piperidine-4-carboxylic acid;

n- (2- (4- (hydroxymethyl) piperidin-1-yl) -5- (trifluoromethyl) phenyl) pyridine carboxamide;

n- (2- (4-hydroxypiperidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

n- (2- (4-hydroxypiperidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4-methylpiperidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

n- (2- (4-methylpiperidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (5-cyclopropyl-2- (4-hydroxypiperidin-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (5-chloro-2- (4-hydroxypiperidin-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4-hydroxypiperidin-1-yl) -5-methylphenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(R) -N- (2- (4-hydroxy-4-methylazepan-1-yl) -5- (trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

(S) -N- (2- (4-hydroxy-4-methylazepan-1-yl) -5- (trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

(R) -N- (5-chloro-2- (4-hydroxy-4-methylazepan-1-yl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

(S) -N- (5-chloro-2- (4-hydroxy-4-methylazepan-1-yl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

(R) -N- (5-cyclopropyl-2- (4-hydroxy-4-methylazepan-1-yl) phenyl) -5- (pyridin-4-yl) -furan-2-carboxamide;

(S) -N- (5-cyclopropyl-2- (4-hydroxy-4-methylazepan-1-yl) phenyl) -5- (pyridin-4-yl) -furan-2-carboxamide;

(R) -N- (2- (4-hydroxy-4-methylazepan-1-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(S) -N- (2- (4-hydroxy-4-methylazepan-1-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(R) -N- (5-chloro-2- (4-hydroxy-4-methylazepan-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(S) -N- (5-chloro-2- (4-hydroxy-4-methylazepan-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(R) -N- (5-cyclopropyl-2- (4-hydroxy-4-methylazepan-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(S) -N- (5-cyclopropyl-2- (4-hydroxy-4-methylazepan-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(R) -N- (2- (4-hydroxyazepan-1-yl) -5- (trifluoromethyl) -phenyl) pyridinecarboxamide;

(S) -N- (2- (4-hydroxyazepan-1-yl) -5- (trifluoromethyl) -phenyl) pyridinecarboxamide;

(R) -N- (2- (4-hydroxyazepan-1-yl) -5- (trifluoromethyl) -phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

(S) -N- (2- (4-hydroxyazepan-1-yl) -5- (trifluoromethyl) -phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

(R) -N- (5-chloro-2- (4-hydroxyazepan-1-yl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

(S) -N- (5-chloro-2- (4-hydroxyazepan-1-yl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

(R) -N- (5-cyclopropyl-2- (4-hydroxyazepan-1-yl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

(S) -N- (5-cyclopropyl-2- (4-hydroxyazepan-1-yl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

(R) -N- (2- (4-hydroxyazepan-1-yl) -5- (trifluoromethyl) -phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(S) -N- (2- (4-hydroxyazepan-1-yl) -5- (trifluoromethyl) -phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(R) -N- (5-chloro-2- (4-hydroxyazepan-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(S) -N- (5-chloro-2- (4-hydroxyazepan-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(R) -N- (5-cyclopropyl-2- (4-hydroxyazepan-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(S) -N- (5-cyclopropyl-2- (4-hydroxyazepan-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(R) -N- (2- (3-hydroxy-3-methylpyrrolidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(S) -N- (2- (3-hydroxy-3-methylpyrrolidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(R) -N- (2- (3-hydroxy-3-methylpyrrolidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

(S) -N- (2- (3-hydroxy-3-methylpyrrolidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

(R) -N- (2- (3-hydroxy-3-methylpyrrolidin-1-yl) -5-methylphenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(S) -N- (2- (3-hydroxy-3-methylpyrrolidin-1-yl) -5-methylphenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(R) -N- (5-cyclopropyl-2- (3-hydroxy-3-methylpyrrolidin-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(S) -N- (5-cyclopropyl-2- (3-hydroxy-3-methylpyrrolidin-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(R) -N- (5-chloro-2- (3-hydroxy-3-methylpyrrolidin-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(S) -N- (5-chloro-2- (3-hydroxy-3-methylpyrrolidin-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(R) -N- (2- (3-hydroxy-3-methylpyrrolidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(S) -N- (2- (3-hydroxy-3-methylpyrrolidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(R) -N- (2- (3-hydroxy-3-methylpyrrolidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

(S) -N- (2- (3-hydroxy-3-methylpyrrolidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

(R) -N- (2- (3-hydroxypyrrolidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

(S) -N- (2- (3-hydroxypyrrolidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

(R) -N- (2- (3-hydroxypyrrolidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

(S) -N- (2- (3-hydroxypyrrolidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4, 4-dimethylpiperidin-1-yl) -5-methylphenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (5-cyclopropyl-2- (4, 4-dimethylpiperidin-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (5-chloro-2- (4, 4-dimethylpiperidin-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4- (hydroxymethyl) -4-methylpiperidin-1-yl) -5-methylphenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (5-cyclopropyl-2- (4- (hydroxymethyl) -4-methylpiperidin-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (5-chloro-2- (4- (hydroxymethyl) -4-methyl-piperidin-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

N- (5-chloro-2- (4- (cyclopropylmethyl) -4-hydroxypiperidin-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4- (cyclopropylmethyl) -4-hydroxypiperidin-1-yl) -5-methylphenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (5-cyclopropyl-2- (4- (cyclopropylmethyl) -4-hydroxypiperidin-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

4-methyl-1- (2- (5- (pyridin-4-yl) furan-2-carboxamido) -4- (trifluoromethyl) phenyl) -piperidine-4-carboxamide;

n, 4-dimethyl-1- (2- (5- (pyridin-4-yl) furan-2-carboxamido) -4- (trifluoromethyl) phenyl) -piperidine-4-carboxamide;

n, 4-trimethyl-1- (2- (5- (pyridin-4-yl) furan-2-carboxamido) -4- (trifluoromethyl) phenyl) -piperidine-4-carboxamide;

4-methyl-1- (2- (5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamido) -4- (trifluoromethyl) -phenyl) piperidine-4-carboxamide;

n, 4-dimethyl-1- (2- (5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamido) -4- (trifluoromethyl) -phenyl) piperidine-4-carboxamide;

n, 4-trimethyl-1- (2- (5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamido) -4- (trifluoromethyl) -phenyl) piperidine-4-carboxamide;

n- (2- (4- (aminomethyl) -4-methylpiperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

N- (2- (4-methyl-4- ((methylamino) -methyl) piperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

n- (2- (4- ((dimethylamino) methyl) -4-methyl-piperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

n- (2- (4- (aminomethyl) -4-methylpiperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4-methyl-4- ((methylamino) methyl) -piperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4- ((dimethylamino) methyl) -4-methyl-piperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

1- (4-chloro-2- (5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamido) phenyl) -N, 4-trimethyl-piperidine-4-carboxamide;

1- (4-methoxy-2- (5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamido) phenyl) -N, 4-trimethyl-piperidine-4-carboxamide;

1- (4-cyclopropyl-2- (5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamido) phenyl) -N, 4-trimethyl-piperidine-4-carboxamide;

n, 4-trimethyl-1- (4-methyl-2- (5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamido) phenyl) piperidine-4-carboxamide;

N- (2- (4-methyl-4- (pyrrolidine-1-carbonyl) -piperidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4-methyl-4- (piperidine-1-carbonyl) -piperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4-methyl-4- (morpholine-4-carbonyl) -piperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (5-chloro-2- (4- ((dimethylamino) methyl) -4-methylpiperidin-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4- ((dimethylamino) methyl) -4-methyl-piperidin-1-yl) -5-methoxyphenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (5-cyclopropyl-2- (4- ((dimethylamino) methyl) -4-methylpiperidin-1-yl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4- ((dimethylamino) methyl) -4-methyl-piperidin-1-yl) -5-methylphenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4-methyl-4- (pyrrolidin-1-ylmethyl) piperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4-methyl-4- (piperidin-1-ylmethyl) piperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

N- (2- (4-methyl-4- (morpholinomethyl) piperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (8-azaspiro [4.5] decan-8-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (2-methyl-2, 8-diazaspiro [4.5] decan-8-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (2-methyl-1-oxo-2, 8-diazaspiro [4.5] decan-8-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4-amino-4-methylpiperidin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (4-amino-4-methylpiperidin-1-yl) -5- (trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

n- (2- (2-methyl-2, 8-diazaspiro [4.5] decan-8-yl) -5- (trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

n- (2- (2-methyl-1-oxo-2, 8-diazaspiro [4.5] decan-8-yl) -5- (trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

n- (2- (2-methyl-2, 8-diazaspiro [4.5] decan-8-yl) -5- (chloro) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

N- (2- (2-methyl-1-oxo-2, 8-diazaspiro [4.5] decan-8-yl) -5- (chloro) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (2-methyl-2, 8-diazaspiro [4.5] decan-8-yl) -5- (methyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (2-methyl-1-oxo-2, 8-diazaspiro [4.5] decan-8-yl) -5- (methyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (2-methyl-2, 8-diazaspiro [4.5] decan-8-yl) -5- (cyclopropyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (2-methyl-1-oxo-2, 8-diazaspiro [4.5] decan-8-yl) -5- (cyclopropyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (2-methyl-2, 9-diazaspiro [5.5] undec-9-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

n- (2- (2-methyl-2, 9-diazaspiro [5.5] undec-9-yl) -5- (trifluoromethyl) phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide.

The general formula (I) is defined herein as follows:

“C _1-6 an alkyl group "refers to a linear or branched alkyl group containing one to six carbon atoms, which is a monovalent group derived by removing any hydrogen atom in an aliphatic hydrocarbon composed of one to six carbons. Specifically, C _1-6 Alkyl groups include, for example: methyl, ethyl, 1-propyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-butyl, 2-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2-dimethyl-1-propyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-methyl-3-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-dimethyl-1-butyl, 2-ethyl-1-butyl, 3-dimethyl-2-butyl and 2, 3-dimethyl-2-butyl.

Herein, the phrase "may have one or more substituents" means that a group or compound may optionally have any selection or combination of one or more substituents at substitutable positions. Specifically, the substituents may include, for example: an atom or group selected from one or more of the following groups: halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, nitro, cyano, formyl, carboxyl, trifluoromethyl, trifluoromethoxy, amino, oxygen, imino, C _1-6 Alkyl (e.g. methyl), C _1-6 Alkoxy (e.g., methoxy), C _1-6 Thioalkyl (e.g., thiomethyl), C _2-6 Alkenyl, C _2-6 Alkynyl; c (C) _1-6 Alkoxycarbonyl group, C _1-6 Alkylsulfonyl, C _5-10 Cycloalkyl, C _5-10 Heterocycloalkyl, C _5-10 Aryl, benzyl, heteroaryl, phenyl, or C substituted with one or more of the following groups _5-10 Cycloalkyl group,C _5-10 Heterocycloalkyl, C _5-10 Aryl or benzyl or phenyl or heteroaryl: halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, nitro, cyano, formyl, carboxyl, trifluoromethyl, trifluoromethoxy, amino, oxygen, imino, C _1-6 Alkyl (e.g. methyl), C _1-6 Thioalkyl (e.g. thiomethyl), C _2-6 Alkenyl, C _2-6 Alkynyl; c (C) _1-6 Alkoxycarbonyl group, C _1-6 Alkylsulfonyl, or C _1-6 Alkoxy (e.g., methoxy).

“C _2-6 Alkenyl "refers to a linear or branched alkenyl group comprising two to six carbons. Specifically, C _2-6 Alkenyl groups include, for example: vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl and hexenyl.

“C _2-6 Alkynyl "refers to a linear or branched alkynyl group containing two to six carbons. Specifically, C _2-6 Alkynyl groups include, for example: ethynyl, 1-propynyl, 2-propynyl, butynyl, pentynyl and hexynyl.

“C _1-6 Alkoxy "means having attached thereto" C "as defined above _1-6 An oxygen group of an alkyl ". Specifically, C _1-6 Alkoxy groups include, for example: methoxy, ethoxy, 1-propoxy, 2-methyl-1-propoxy, 2-methyl-2-propoxy, 1-butoxy, 2-butoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 2-methyl-1-butoxy, 3-methyl-1-butoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 2-dimethyl-1-propoxy, 1-hexoxy, 2-hexoxy, 3-hexoxy, 2-methyl-1-pentoxy, 3-methyl-1-pentyloxy, 4-methyl-1-pentyloxy, 2-methyl-2-pentyloxy, 3-methyl-2-pentyloxy, 4-methyl-2-pentyloxy, 2-methyl-3-pentyloxy, 3-methyl-3-pentyloxy, 2, 3-dimethyl-1-butoxy, 3-dimethyl-1-butoxy, 2-dimethyl-1-butoxy, 2-ethyl-1-butoxy, 3-dimethyl-2-butoxy, and 2, 3-dimethyl-2-butoxy.

“C _1-6 Thioalkyl "means having attached thereto" C "as defined above _1-6 Alkyl "sulfur groups. Specifically, "C _1-6 Thioalkyl "includes, for example: thiomethyl, thioethyl, 1-thiopropyl, 2-thiopropyl, thiobutyl and thiopentyl.

“C _1-6 Alkoxycarbonyl "means having attached thereto" C "as defined above _1-6 Carbonyl groups of alkoxy ". Specifically, C _1-6 Alkoxycarbonyl groups include, for example: methoxycarbonyl, ethoxycarbonyl, 1-propoxycarbonyl and 2-propoxycarbonyl.

“C _1-6 Alkylsulfonyl "means having attached thereto" C "as defined above _1-6 Sulfonyl groups of alkyl ". Specifically, C _1-6 Alkylsulfonyl groups include, for example: methylsulfonyl, ethylsulfonyl, 1-propylsulfonyl and 2-propylsulfonyl.

"heterocycle" or "heterocyclic group" refers to an aromatic or non-aromatic ring that may contain a double bond within the ring, wherein at least one (e.g., one or two) of the atoms making up the ring is a heteroatom.

"heteroatom" means a sulfur atom, an oxygen atom, or a nitrogen atom.

Detailed Description

The compounds of the present invention are inhibitors of SRPK1 specificity and thus may be used in methods of treating or preventing any disease or condition involving SRPK 1. These conditions and methods of treatment will be described below. Nor do these compounds inhibit any of CYP1A2, CYP2C9, CYP2C129, CYP2D6 or CYP3A4 to any clinically significant extent and are therefore particularly useful for systemic administration for the treatment or prevention of any of the diseases or conditions described herein.

Anti-angiogenic therapy

The compounds of the invention are useful in anti-angiogenic therapies. The anti-angiogenic therapy preferably includes the treatment or prevention of a disorder associated with aberrant angiogenesis or pro-angiogenic VEGF isoforms (VEGF) _xxx ) Any disease or disorder associated with abnormal overproduction of (c). These diseases and disorders include, for example: vascular diseases (e.g., vasoconstriction and disorders characterized by vasoconstriction, cardiovascular diseases), malignancies andbenign neoplasia (e.g., angiogenesis-dependent cancers, e.g., tumor cancers), tumor metastasis, inflammatory disorders, diabetes, diabetic retinopathy and other complications of diabetes (e.g., diabetic neovascularization or diabetic macular edema), particulate conjunctivitis, retrolental hyperplasia, neovascular glaucoma, age-related macular degeneration, macular edema, hemangiomas, immune rejection of implanted corneal tissue, corneal angiogenesis associated with ocular injury or infection, osler-Webber Syndrome (Osler-Webber Syndrome), myocardial angiogenesis, wound bed granulation, telangiectasia, hemophilia joints, vascular fibromas, telangiectasia, psoriasis, scleroderma, suppurative granuloma, flushing, obesity, arthritis (e.g., rheumatoid arthritis), hematopoiesis, gingivitis, atherosclerosis, endometrium, neointimal hyperplasia, psoriasis, multiple hair-up and proliferative retinopathy. Anti-angiogenic therapies according to the invention may also include non-therapeutic therapies administered on healthy subjects, e.g., to inhibit vascular development for cosmetic purposes. For a detailed description of diseases and disorders associated with aberrant angiogenesis, see WO2008/110777, the contents of which are incorporated herein by reference.

In particular, the compounds of the invention are useful for treating or preventing ocular neovascularization, which can include retinal neovascularization or choroidal neovascularization, such as age-related macular degeneration or macular edema. Furthermore, the compounds of the invention are useful for the treatment or prevention of malignant neoplasias or cancers, e.g., prostate and breast cancers.

Microvascular hyperpermeability disorders, epithelial cell survival disorders and epithelial filter membrane fenestration disorders

The compounds of the invention as SRPK1 inhibitors are also useful as therapeutics for VEGF involved in alternative splicing _xxx b therapeutic agents for other diseases of the genotype. For example, WO2010/058227 (the disclosure of which is incorporated herein by reference) has disclosed VEGF _xxx b for multiple microvascular hyperpermeability disorders, epithelial cellsSurvival and epithelial filter membrane fenestration are active.

Microvascular hyperpermeability, modulation of VEGF _xxx Deregulation of pro-angiogenic pro-permeability properties of the isoforms, deregulation of epithelial cell survival and permeability and/or deregulation of epithelial filter membrane fenestration characteristics (e.g., number density and/or size) and/or modulation of endothelial cell glycocalyx (e.g., thickness, charge, chemical composition-generated in situ or absorbed from plasma) are the basis for a variety of serious medical conditions and hypertonic states.

Examples of such conditions include, for example: proteinuria, uremia, microalbuminuria, hypoalbuminemia, renal ultrafiltration, nephrotic syndrome, renal failure, pulmonary hypertension, capillary hyperpermeability, arteriolar tumors, cerebral edema and diabetic vascular complications.

Examples of such diabetic vascular complications include, for example: diabetic retinopathy (proliferative and non-proliferative) and diabetic nephropathy. Diabetic vascular complications may be associated with type I diabetes or type II diabetes.

The loss of proteins in the blood can lead to other complications such as thrombosis (especially in the brain) and susceptibility to infection. The loss of natural proteins in the blood can severely impair the efficacy of cancer treatment.

The microvascular hyperpermeability disorder may specifically be a kidney disease, e.g., a GFB permeability disorder, e.g., a podocyte permeability disorder.

Examples of disorders for which treatment supporting epithelial cell survival would be effective are as follows:

systemic capillary infiltration, acute pulmonary fibrosis, adult respiratory distress syndrome, advanced cancer, allergic respiratory diseases, alveolar injury, angiogenesis, arthritis, ascites, asthma, post burn asthma or edema, atherosclerosis, autoimmune diseases, bone resorption, bullous diseases associated with subepithelial vesicular formation (including bullous pemphigoid), cardiovascular diseases, some renal diseases associated with proliferation of glomerular or mesangial cells, chronic and allergic inflammation, chronic lung disease, chronic obstructive pulmonary disease, cirrhosis, corneal angiogenesis, corneal diseases, coronary and cerebral collateral angiogenesis, coronary restenosis, post-cardiac injury, dermatitis herpetiformis, diabetes, diabetic nephropathy, diabetic retinopathy, endotoxin shock, erythema multiforme, fibrosis, glomerulonephritis, graft rejection, gram negative sepsis, hemangioma, cirrhosis, liver failure, shingles, graft versus host reaction (ischemia reperfusion injury and allograft rejection of kidney, liver, heart and skin), poor wound healing of infection, herpes simplex infection, human Immunodeficiency Virus (HIV) infection, inflammation, cancer, inflammatory bowel disease (Crohn's disease and ulcerative colitis), inflammatory disorders, restenosis in stents, stenosis in stents, ischemia, ischemic retinal vein occlusion, ischemic retinopathy, kaposi's sarcoma, keloids, acute inflammatory liver disease, lung allograft rejection (obstructive bronchitis), lymphoid malignancies, macular degeneration retinopathy of prematurity, myelodysplastic syndrome, myocardial angiogenesis, neovascular glaucoma, non-insulin dependent diabetes mellitus (NIDDM), obstructive bronchiolitis, ocular disorders or diseases, ocular diseases associated with retinal vascular proliferation, osier-Weber-Rendu disease, osteoarthritis, ovarian hyperstimulation syndrome, bai Zhede (Paget) disease, pancreatitis, pemphigoid, polycystic kidney disease, polyps, postmenopausal osteoporosis, preeclampsia, psoriasis, pulmonary edema, pulmonary fibrosis, pulmonary sarcoidosis, restenosis, retinopathy including diabetic retinopathy, retinopathy of prematurity and senile macular degeneration, rheumatoid arthritis, flushing, sarcoidosis, sepsis, stroke, synovitis, systemic lupus erythematosus, thyroiditis, thrombotic microvascular syndrome, graft rejection, trauma, tumor-associated angiogenesis, vascular graft restenosis, hill-lin (von Hippel Lindau) syndrome, wound healing.

The invention can be used for treating macular dystrophy. This includes: stargardt disease/ocular fundus yellow spot, stargardt-like macular dystrophy; stargardt-like macular dystrophies; autosomal dominant "target eye" macular dystrophy, best macular dystrophy; egg yolk malnutrition in adults; pattern dystrophy, doyne honeycomb retinal dystrophy; north Carolina macular dystrophy; MCDR 1-like autosomal dominant macular dystrophy; north Carolina-like macular dystrophies associated with hearing loss; progressive bifocal chorioretinal atrophy; sorsby fundus dystrophy; central halo choroidal dystrophy; dominant cystic macular odema; teenager retinal split disease; hidden macular dystrophy; non-familial occult macular dystrophy.

The disease may in particular be a retinal epithelial cell disease, for example geographic atrophy or age-related macular degeneration.

For a further detailed description of microvascular hyperpermeability disorders, epithelial cell survival disorders and epithelial filter membrane fenestration disorders, see WO2010/058227, the disclosure of which is incorporated herein by reference.

Neurological and neurodegenerative disorders

The compounds of the invention as SRPK1 inhibitors are also useful as therapeutics for VEGF involved in alternative splicing _xxx b therapeutic agents for other diseases of the genotype. For example, WO2009/106855 (the disclosure of which is incorporated herein by reference) has disclosed VEGF _xxx b has neuroprotective and nerve regenerating effects.

The neurological disorders to be treated or prevented according to the present invention include neuropathic pain and diabetic neuropathy, among others.

Neurodegenerative disorders to be treated or prevented according to the present invention include cognitive and non-cognitive neurodegeneration, neuromuscular degeneration, motor sensory neurodegeneration, ocular neurodegeneration.

It is envisioned that VEGF _xxx The activity of proteins of the b family is effective in preventing and effectively reversing the conditions and disorders.

Moreover, because mild cognitive impairment is often associated with the normal state of a certain class of healthy humans, e.g., elderly, people under stress, tired or tired, the present invention may also be applied to non-therapeutic treatment of healthy humans to regulate or normalize their cognitive function and behavior, including thinking, memory, learning, concentration and reasoning.

Moreover, because nerve regeneration may help normalize the brain neural network in subjects with mental or behavioral abnormalities, whether or not these are diagnosable for one or more identified mental disorders, the present invention may also be applied to therapeutic treatment of humans with mental disorders as well as non-therapeutic treatment of healthy humans, thereby regulating their cognition and behavior to a normal state.

For example, the invention provides the treatment or prevention of the following diseases: pain (e.g., neuropathic pain), dementia, senile cognitive impairment, alzheimer's disease, alzheimer's type Senile Dementia (SDAT), louis's body loss of intelligence, vascular dementia, parkinson's disease, postencephalitis Parkinson's syndrome, depression, schizophrenia, muscular dystrophy (including facial shoulder humeral muscular dystrophy (FSH)), duchenne muscular dystrophy, beck muscular dystrophy and Bruce muscular dystrophy, fuchs dystrophy, myotonic dystrophy, corneal dystrophy, reflex Sympathetic Dystrophy Syndrome (RSDSA), neurovascular dystrophy, myasthenia gravis, lambert Eaton disease, huntington's disease, motor neuron disease (including Amyotrophic Lateral Sclerosis (ALS)), multiple sclerosis, in-vivo hypotension, traumatic neuropathy or neurodegeneration (e.g., post-stroke or post-accident (e.g., traumatic head injury or spinal cord injury)), basteng's disease, kochia syndrome, down's syndrome, corticobasal ganglion degeneration, multiple system atrophy, brain atrophy, olive brain pontic cerebellar atrophy, dentate nucleus red nucleus atrophy, globus pallidus, spinal bulbar atrophy, optic neuritis, sclerotic panencephalitis (SSPE), attention deficit syndrome, postviral encephalitis, poliomyelitis postsyndrome, french syndrome, zhu Bate syndrome, guillain-Barre syndrome, no brain return deformity, smoke disease, neuronal migration disorder, autism, polyglutamine disease, niemann-Pick disease, progressive multifocal leukoencephalopathy, pseudoencephaloma, refsum disease, zellweger syndrome, supranuclear palsy, friedreich's ataxia, spinocerebellar ataxia type 2, rett (Rhett) syndrome, shy-Drager syndrome, tuberous sclerosis, pick's disease, chronic fatigue syndrome, neuropathy (including hereditary neuropathy, diabetic neuropathy and mitotic neuropathy), prion-based neurodegeneration (including Creutzfeldt-Jakob, CJD), anamorphic CJD, newly anamorphic d, bovine Spongiform Encephalopathy (BSE), GSS, FFI, bitter and alpepeis syndrome (Alper's syndom)), joseph's disease, acute disseminated encephalomyelitis, arachnoid inflammation, central nervous system vascular neuropathy, neuronal loss, extreme-motor-three-phase disease, eye degeneration, maculopathy, visual degeneration, such as krighlegmann's disease, kriging's disease, focal degeneration.

In general, mental disorders are not diagnosed as "mental disorders" unless the associated behavior or idea is damaging to his or her daily behavior or is producing significant adverse stress to the individual. Thus, there is a boundary between diagnosable diseases and similar diseases, but treatments for less severe or less damaging psychological functions should be considered non-therapeutic (see below).

Examples of mental disorders for which the present invention is directed include, but are not limited to: anxiety disorders (e.g., acute stress disorder, panic disorder, agoraphobia, social phobia, specific subject phobia, obsessive compulsive disorder, sexual anxiety disorder, post traumatic stress disorder, physical deformity phobia and generalized anxiety disorder), childhood disorders (e.g., attention Deficit Hyperactivity Disorder (ADHD), sub-singer's syndrome, autism, behavioral disorders, oppositional defiant disorder, separation anxiety disorder and tourette's syndrome), eating disorders (e.g., anorexia nervosa and binge eating disorder), mood disorders (e.g., depression, major depression, bipolar disorder (manic-depressive disorder), seasonal Affective Disorder (SAD), circulatory mood disorder and depression), sleep disorders, cognitive mental disorders (e.g., confusion, amnesia), personality disorders (e.g., delusional personality disorder, schizopersonality disorder, antisocial personality disorder, borderline personality disorder, performance personality disorder, self-loving personality disorder, avoidance personality disorder, dependent personality disorder, and obsessive-compulsive personality disorder), psychotic disorders (e.g., schizophrenia, delusional disorder, brief psychotic disorder, schizoaffective disorder, and shared psychotic disorder), and substance-related disorders (e.g., alcohol dependence, amphetamine dependence, cannabis dependence, cocaine dependence, hallucinogen dependence, inhalant dependence, nicotine dependence, opioid dependence, phencyclidine dependence, and sedative dependence).

For a further detailed description of neurological and neurodegenerative disorders see WO2009/106855, the disclosure of which is incorporated herein by reference.

Treatment of pain

The compounds of the invention as SRPK1 inhibitors are also useful as therapeutics for VEGF involved in alternative splicing _xxx b therapeutic agents for other diseases of the genotype. The compounds of the invention as SRPK1 inhibitors are useful for alleviating pain, for example, in subjects experiencing pain due to nerve damage or other neuronal abnormalities. The compounds of the invention as SRPK1 inhibitors are also useful for alleviating pain in subjects experiencing pain without nerve damage or other neuronal abnormalities. The compounds of the invention as SRPK1 inhibitors are useful for alleviating inflammatory or non-inflammatory pain in a subject experiencing pain. For example, WO2011/148200 (the disclosure of which is incorporated herein by reference) has disclosed VEGF _xxx b have analgesic effect on VEGFR 2-mediated non-inflammatory pain in mammals.

VEGFR 2-mediated non-inflammatory pain to be treated or prevented according to the invention includes non-inflammatory neuropathic pain and nociceptive pain, wherein the VEGFR2 receptor is involved in the cause or transmission of pain. For example, it is contemplated that compounds according to the present invention are active against non-inflammatory allodynia and pain (analgesic and analgesic activity).

This type of pain state includes chronic pain, whether intermittent or persistent. Such pain states may include, for example: lower back pain, neuralgia, atypical pain (e.g., atypical facial pain), postoperative pain, post-injury pain (e.g., following surgery or injury resulting in nerve injury) or pain associated with cancer or cancer therapy (e.g., cytotoxic therapy or radiation therapy), or diabetes-related neuropathy (diabetic neuropathy, insulin neuritis) or other systemic or autoimmune diseases or pathologies, or treatments for them, alcoholism or HIV infection, senile neuropathy or neuropathy of unknown origin.

It is contemplated that VEGFR2 agonists (e.g., VEGF _xxx The activity of the proteins of family b) is effective in preventing and reversing VEGFR 2-mediated non-inflammatory pain. However, VEGF-based _xxx Anti-angiogenic activity of b-family proteins the use of the compounds of the invention will be limited to pain in cases where possible inhibition of angiogenesis is not harmful to the patient.

The compounds used in the present invention may be used in combination with one or more different pain therapeutic agents to normalize sensitivity to pain in a subject being treated (or co-treated) with the one or more different pain therapeutic agents. The term "normalization" refers to shifting the subject's pain sensitivity to normal levels, and may include increasing the sensitivity if the one or more different pain therapeutic agents result in an excessive reduction in the sensation or sensitivity to pain.

The one or more different pain therapeutic agents may be selected from currently known pain therapeutic agents or pain therapeutic agents to be designed. Such choices are within the level of skill of one of ordinary skill in the art. Such combination therapy enables precise control of pain sensitivity in a subject and minimizes systemic side effects depending on the specific condition and need of the subject.

For further details on pain and its treatment see WO2011/148200, the disclosure of which is incorporated herein by reference.

Reducing risk of preeclampsia

The compounds of the invention as SRPK1 inhibitors are also useful as therapeutics for VEGF involved in alternative splicing _xxx b therapeutic agents for other diseases of the genotype. For example, WO2011/036429 (the disclosure of which is incorporated herein by reference) has disclosed reduced VEGF in pregnant female mammals _xxx b levels increase the risk of a female mammal to develop preeclampsia.

Thus, the compounds of the invention are useful for increasing VEGF in pregnant female mammals _xxx b to reduce the risk of a female mammal developing preeclampsia or complications associated therewith, or a fetus of a female mammal developing a fetal or neonatal deficiency associated with maternal preeclampsia.

Preeclampsia in humans can occur at the earliest 20 weeks of gestation. Preeclampsia occurring 34 weeks prior to gestation is commonly referred to as "early pre-eclampsia" or "early-onset preeclampsia". Preeclampsia occurring 34 weeks after gestation is commonly referred to as "late pre-eclampsia" or "late-onset preeclampsia". Furthermore, preeclampsia may be classified as "severe preeclampsia" according to the criteria established by the department of obstetrics and gynecology of Royal, england. According to these criteria, a patient with "severe preeclampsia" will have either a systolic pressure (BP) greater than 169mmHg or a diastolic pressure (BP) greater than 109mmHg, with proteinuria exceeding 1g/24 hours; or HELLP syndrome (hemolysis, elevated liver enzymes and reduced platelet count) will occur.

For more details on preeclampsia, and methods of reducing the risk of a pregnant female mammal developing preeclampsia or complications associated therewith, or a fetus of a female mammal developing a fetal or neonatal deficiency associated with maternal preeclampsia, see WO2011/036429, the disclosure of which is incorporated herein by reference.

Active compounds

The compounds of the present invention are defined by general formula (I) and have been shown to be inhibitors of kinase SRPK1 and, therefore, are useful in the treatment described herein. The compounds of the present invention may be synthesized by any known method. Exemplary synthetic methods are described in the examples section below.

Combination administration

If desired, the compounds of the present invention may be administered in combination with one or more additional active agents, for example, one or more active agents selected from, but not limited to: cholinesterase inhibitors, dopamine agonists (e.g., levodopa), COMT inhibitors, MAO-B inhibitors, anti-cholinergic agents, acetylcholine agonists, serotonin agonists, AMPA receptor agonists, GABA receptor agonists, NMDA receptor agonists, beta-adrenergic receptor agonists, digoxin, dobutamine, anti-inflammatory agents, neurotrophic factors, statins, adenosine A2a receptor antagonists, aldose reductase inhibitors, immunomodulators, cannabinoid agonists, interferons or tricyclic antidepressants.

Salts, solvates, hydrates and prodrugs

In the present invention, "salt" is not particularly limited as long as the salt is a pharmaceutically acceptable salt formed from the compound according to the present invention. These salts include, for example: inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, and acidic or basic amino acid salts.

Examples of preferred inorganic acid salts include: hydrochloride, hydrobromide, sulfate, nitrate and phosphate. Examples of preferred organic acid salts include: acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, methylsulfonate and para-toluenesulfonate. Examples of preferred inorganic base salts include: alkali metal salts, for example, sodium and potassium salts; alkaline earth metal salts, for example, calcium and magnesium salts; an aluminum salt; and ammonium salts. Examples of preferred organic base salts include: diethylamine salt, diethanolamine salt, meglumine salt and N, N' -dibenzylethylenediamine salt. Examples of preferred acidic amino acid salts include: aspartate and glutamate. Examples of preferred basic amino acid salts include: arginine salts, lysine salts and ornithine salts.

When the compound of the present invention is left in the air, the compound of the present invention sometimes absorbs moisture and sometimes adheres to the absorbed moisture or converts to a hydrate. The hydrates are also included in the present invention.

Moreover, the compounds of the present invention sometimes absorb some of the other solvents and convert to solvates. Such solvates are also included in the present invention.

In principle, any organic solvent may be used to prepare solvates of the compounds of the invention. Solvates may also include water and one or more organic solvents. Thus, for example, the solvent may be selected from: ketone solvents, alcohol solvents, ether solvents, ester solvents, aromatic solvents, and, if possible, mixtures thereof with one another, mixtures thereof with other organic solvents and/or mixtures thereof with water.

Pharmaceutically acceptable prodrug forms of the compounds of formula (I) are useful in the present invention. "pharmaceutically acceptable prodrugs" refer to those prodrugs of a compound that are suitable for use in contact with human tissue and lower animal tissue without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, and are also zwitterionic forms of the compound, where possible, within the scope of sound medical and veterinary judgment. The term "prodrug" refers to the following compounds: which is rapidly converted in vivo to produce the parent compound of the general formula described above, for example, by hydrolysis in blood. Functional groups that can be rapidly converted in vivo by metabolic cleavage form a class of groups that react with carboxyl groups. Since metabolically cleavable groups of compounds are prone to cleavage in vivo, compounds bearing these groups act as prodrugs. A complete discussion of prodrugs is provided in the following references: design of Prodrugs, h.bundegaard, ed., elsevier,1985; methods in Enzymology, K.Widder et al Ed., academic Press,42, p.309-396,1985; a Textbook of Drug Design and Development, krogsgaard-Larsen and h.bundgaard, ed., chapter 5; design and Applications of Prodrugs p.113-191,1991; advanced Drug Delivery Reviews, H.Bundgard,8, p.l-38,1992; journal of Pharmaceutical Sciences,77, p.285,1988; chem.Pharm.Bull., N.Nakeya et al, 32, p.692,1984; pro-drugs as Novel Delivery Systems, T.Higuchi and V.stilla, vol.14of the A.C.S. symposium Series, and Bioreversible Carriers in Drug Design, edward B.Roche, ed., american Pharmaceutical Association and Pergamon Press,1987, incorporated herein by reference.

Compositions and administration

The compounds according to the invention may be administered in the form of a composition comprising the active agent and any suitable other ingredient. For example, the composition may be a pharmaceutical composition (drug) suitable for topical administration (e.g., as an eye drop or cream or emulsion) or systemic administration (e.g., enteral administration (e.g., in the form of a tablet, lozenge, dragee, capsule or liquid) or parenteral administration (e.g., injection, implant or infusion)). For example, the composition may optionally be a food, food supplement, drink, or drink supplement.

"pharmaceutical composition" or "drug" herein refers to a composition comprising an active agent and additionally comprising one or more pharmaceutically acceptable carriers. Based on the mode of administration and the nature of the dosage form, the composition may further comprise an ingredient selected from the group consisting of: for example, diluents, adjuvants, excipients, carriers, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, antibacterial agents, antifungal agents, lubricants and dispersing agents.

For example, the composition may take the form: tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, troches, emulsions, solutions, cachets, granules, capsules and suppositories, and liquid preparations for injection including liposomal preparations. Techniques and dosage forms can generally be found in the following references: remington, the Science and Practice of Pharmacy, mack Publishing co., easton, PA, latest edition.

Formulations in liquid form include solutions, suspensions and emulsions. Examples are water or water-propylene glycol solutions for parenteral injection or topical administration. The liquid formulation may also be formulated in an aqueous polyethylene glycol solution.

The present invention also includes solid form formulations which can be rapidly converted to liquid form formulations prior to use for topical, oral or parenteral administration. The liquid form comprises: solutions, suspensions and emulsions. These particular solid form formulations are most conveniently presented in unit dosage form for use in providing a single liquid dosage unit. Alternatively, sufficient solids may be provided before it is converted to liquid form, such as by measuring a predetermined volume of the liquid form of the formulation from a syringe, teaspoon or other volumetric container or device to obtain a plurality of individual liquid dosage forms. The formulations to be converted into solid form in liquid form may contain, in addition to the active substance, flavouring agents, colouring agents, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilisers and the like. The liquid used to prepare the formulation in liquid form may be water, isotonic water, ethanol, glycerol, propylene glycol, and the like, as well as mixtures thereof. Naturally, the liquid used may be selected according to the route of administration, e.g. liquid formulations comprising large amounts of ethanol are not suitable for topical or parenteral use.

The composition may be in a dosage form for topical administration. The dosage form may be a controlled release gel dosage form and thus may allow the active agent to act upon topical application. The dosage form may comprise one or more gelling agents, for example, hydroxypropyl methylcellulose. The dosage form may comprise one or more surfactants, for example, nonionic liquid polymers, examples of which include: tyloxapol (Tyloxapol) and BASFPoloxamer (poloxamer). The dosage form may comprise one or more solubilising agents, for example dextran or sorbitol. By a means ofThe dosage form may contain one or more antibacterial agents or preservatives, for example benzalkonium chloride. The gelling agents, surfactants, solubilizing agents and antibacterial agents described above are listed by way of example only and other agents for accomplishing these functions are known in the art.

The dosage of the compound used may vary based on the needs of the patient, the severity of the condition being treated, and the compound being used. Determination of the appropriate dosage for a particular situation is within the ability of those skilled in the art. Overall, treatment is started at a smaller dose than the optimal dose of the compound. Thereafter, the dosage is increased in smaller increments until the best effect in the different situations is reached. For convenience, the total daily dose may be divided and administered in multiple portions during the day, if desired.

For example, a dosage regimen for administering an active agent may include a total dose of up to 1 μg, e.g., up to 500ng, e.g., up to 50ng, e.g., less than 20ng of active agent during the administration period (e.g., 1 day to 14 days). For example, a total dose of less than 18ng, 17ng, 16ng, 15ng, 14ng, 13ng, 12ng, 11ng, or 10ng may be administered.

A therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof may be administered. A therapeutically effective amount of a compound of formula (I) for topical administration to treat CNV may be at least about 5 μg/10 μl of the delivery vehicle. Alternatively, a therapeutically effective amount may be at least about 100 μg/mL, e.g., at least about 200 μg/mL, at least about 300 μg/mL, at least about 400 μg/mL, at least about 500 μg/mL, at least about 600 μg/mL, at least about 700 μg/mL, at least about 800 μg/mL, at least about 900 μg/mL, or at least about 1000 μg/mL. Alternatively, a therapeutically effective amount may be at least about 1mg/mL, for example, at least about 2mg/mL, at least about 3mg/mL, at least about 4mg/mL, at least about 5mg/mL. Alternatively, a therapeutically effective amount may be less than about 5mg/mL, for example, less than about 4mg/mL, less than about 3mg/mL, less than about 2mg/mL, less than about 1mg/mL. During the administration period (e.g., 1 day to 14 days), a therapeutically effective amount may be administered daily. The therapeutically effective amount may be the total daily dose which may be administered in multiple divided doses (e.g., twice daily) over the course of a day.

A therapeutically effective amount of a compound of formula (I) may be calculated on the basis of the body weight of the subject to be treated and may be at least about 20mg/kg, for example, at least about 30mg/kg, at least about 40mg/kg, at least about 50mg/kg, at least about 60mg/kg, at least about 70mg/kg, at least about 80mg/kg, at least about 90mg/kg, at least about 100mg/kg, for use in anti-angiogenic therapy in a mammalian subject or for use in the treatment or prevention of microvascular hyperpermeability disorder, or for use in the modulation of VEGF _xxx The pro-angiogenic pro-permeability properties of the isoforms are useful for supporting epithelial cell survival without increasing permeability, or for reducing epithelial filter membrane fenestration characteristics (e.g., number density and/or size), or for treating or preventing neurological or neurodegenerative disorders, or as neuroprotective or neuroregenerative agents in vivo or in vitro, or for treating or preventing VEGFR 2-mediated non-inflammatory pain, or for reducing the risk of pre-eclampsia or complications associated therewith in a female mammal, or the risk of fetal or neonatal defects associated with maternal pre-eclampsia in a fetus in a female mammal. Alternatively, a therapeutically effective amount may be less than about 100mg/kg, for example, less than about 90mg/kg, less than about 80mg/kg, less than about 70mg/kg, less than about 60mg/kg, less than about 50mg/kg, less than about 40mg/kg, less than about 30mg/kg, or less than about 20mg/kg, for example, less than about 10mg/kg, less than about 5mg/kg.

"treatment or prevention"

The term "treatment or prevention" and similar terms as used herein refer to all forms of healthcare intended to remove or avoid a disease or to alleviate symptoms thereof, including prophylactic, curative and palliative treatments, as assessed according to any test available in general medical methods and psychiatric practice. Intervention methods that are intended to reasonably predict the achievement of a particular outcome, but not always making such predictions, are included within the scope of the term "treatment or prevention". Intervention methods that successfully slow or inhibit disease progression are included within the scope of the term "treatment or prevention".

Some neurological and psychiatric disorders are considered "spectrum" disorders, in which individual individuals may exhibit some or all of a number of possible symptoms, or may exhibit only mild forms of the disorder. Moreover, a variety of neurological and psychiatric disorders are progressive, starting with relatively mild abnormal symptoms and progressing to more severe ones. The present invention includes the treatment and prevention of all neurological and psychiatric disorders, regardless of type and stage.

Susceptibility "

The term "susceptibility" and similar terms as used herein refer specifically to an individual at a higher than normal risk of developing a medical or psychiatric disorder or a personality change, as assessed using known risk factors for the individual or disorder. The individual may be categorized as having a substantial risk of suffering from one or more specific diseases or personality changes, for example, to the extent that the medication is prescribed and/or a special diet, lifestyle or similar recommendation may be made for the individual.

"non-therapeutic methods"

The term "non-therapeutic method" as used herein particularly refers to an intervention performed on an individual that is within a normal range of neurologically or psychologically, thereby normalizing or enhancing or improving the function of the neurological or psychological trait.

Neurological functions that may be suitable for non-therapeutic treatment may include, for example: cognition (including thinking, reasoning, memory, recall, imagination and learning), concentration and attention, especially toward the lighter ends of the disorder level and the lighter abnormal behavior or personality traits. Psychological functions that may be suitable for non-therapeutic treatment may include, for example: human behavior, mood, personality, and social functions, such as, for example, sadness, anxiety, depression, mood, depression, adolescent mood, sleep pattern disruption, realistic dreams, nightmares, and night-time swimming.

There is a boundary between diagnosable neurological and psychological disorders and neurological and psychological functions within a normal range of non-diagnosable. Thus, in addition to the examples of neurological and psychiatric functions given above that can be treated according to the non-therapeutic methods of the invention, non-diagnosable minor forms of neurological and psychiatric disorders (because the relevant behavior or ideas do not pose a significant hazard to the individual or do not disrupt his or her daily functioning) are also considered disorders treatable according to the non-therapeutic methods of the invention.

"normalization"

The term "normalization" and similar terms as used herein refer specifically to the physiological modulation of a neurological or psychiatric state of health that is characterized by a general normal, whether or not a state characterized by normal is actually achieved.

A mammal

In addition to use in human therapy, the present invention is also useful in a variety of different mammals. These mammals include, for example, non-human primates in zoos (e.g., apes, monkeys, and lemurs), pets (e.g., cats and dogs), working and arenas (e.g., dogs, horses and ponies), farm animals (e.g., pigs, sheep, goats, deer, bull, and cattle), and laboratory animals (e.g., rodents (e.g., rabbits, rats, mice, hamsters, gerbils, or guinea pigs)). Where the disease or function to be treated is directed to humans only, it is to be understood that the mammal to be treated is a human. Likewise, this applies to any other mammalian species, respectively, if the disease or function to be treated is only for those species.

Drawings

For purposes of illustration only, embodiments of the invention will be described with reference to the accompanying drawings, in which:

fig. 1 (a) and 1 (b) show the effect of the compounds of the invention on lesion size in a laser induced mouse CNV model.

Method

Synthetic protocol

General synthetic protocols for compounds are shown in schemes 1-3 and described in detail below, wherein substituents are defined herein. This protocol may be altered to synthesize other compounds described herein, which alterations are within the ability of those skilled in the art.

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General procedure 1-aromatic nucleophilic substitution reaction

A solution of substituted nitrobenzene 1 (1 eq), saturated nitrogen heterocycle 2 (1.1 eq) and solid sodium carbonate (2.5 eq) in anhydrous THF (3M) was heated to reflux for 16h. The solution was cooled to room temperature, the reaction solution was filtered through a celite pad, and eluted with ethyl acetate. The organic filtrate was concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel using a mixture of ethyl acetate and n-hexane as eluent to give the title product 2 (x=cl, CF ₃ 、OMe、OCF ₃ 、Me、CHF ₂ )。

General procedure 2-Synthesis of cyclopropane Components

Palladium (II) acetate (4.65 mol%) and X-phosphorus (X-phos) (10 mol%) were added to a stirred suspension of chlorine compound 3 (0.35 g,1.29 mmol), cyclopropylboronic acid (3.8 eq.) and potassium carbonate (3 eq.) in THF (0.18M). After purging with nitrogen for 30min, the resulting reaction mixture was heated to 70 ℃ and held for 2h. The reaction mixture was cooled to room temperature, then the reaction mixture was filtered through a pad of celite, eluting with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was poured into water (30 ml), and extracted with ethyl acetate (×3). The organic extracts were mixed and washed with brine, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel using a mixture of ethyl acetate and n-hexane as eluent to give the title product 3 (x=cyclopropyl).

General procedure 3-reduction of nitro Compounds

Hydrazine hydrate (25 eq.) was added dropwise to compound 2 (x=cl, CF) at 0 °c ₃ ，OMe，OCF ₃ ，Me，CHF ₂ ) Or a methanol (0.1M) solution of compound 3 (x=cyclopropyl) (1 equivalent), ferric trichloride hexahydrate (0.24 equivalent) and charcoal (0.05 g/mmol starting material). The resulting reaction mixture was heated under reflux for 1h. The reaction mixture was cooled to room temperature, then the reaction mixture was filtered through a pad of celite, eluting with ethyl acetate. The filtrate was removed under reduced pressure. The residue was diluted with water (70 ml) and extracted with ethyl acetate (×3). The organic extracts were mixed and dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure, and the resulting crude product was purified by flash chromatography on silica gel using a mixture of ethyl acetate and n-hexane as an eluent to obtain the title product 4.

General procedure 4-Synthesis of 5- (4-pyridyl) furan analogs (examples 4-10, 24, 26, 28, 32, 34, 37-42, 52-53, 55-56)

(a) Triethylamine (2 eq) and T3P (1.5 eq) were added to a solution of aniline (1 eq) and 5-bromofuran-2-carboxylic acid (1.2 eq) in ethyl acetate (0.25M) from general step 3. The resulting reaction mixture was heated to reflux for 2h. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic extracts were mixed and dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel using a mixture of ethyl acetate and n-hexane as eluent to obtain the title product.

(b) Bromide (1.3 eq), pyridine-4-boronic acid (1 eq), pdCl under nitrogen atmosphere ₂ (PPh ₃ ) ₂ (0.042 eq.) a solution of 1, 2-dimethoxyethane (0.08M) in 2M aqueous sodium carbonate (2.8 eq.) was heated under reflux for 17h. The reaction mixture was cooled to room temperature and excess DME was removed under reduced pressure. The pH of the residue was adjusted to pH 1 with 2M aqueous hydrochloric acid. The solution was extracted with dichloromethane (×3). The dichloromethane extract was discarded. Neutralizing the remaining aqueous solution with solid sodium bicarbonate to pH.about.9, and extracted with ethyl acetate (. Times.3). The organic extracts were combined, washed with water and brine, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel using a mixture of ethyl acetate and n-hexane as eluent to obtain the title product.

General procedure 5-Aniline acylation (examples 1-3, 11-23, 25, 27, 29-31, 33, 35-36, 40-42, 50-51, 57)

Triethylamine (2 eq) and T3P (1.5 eq) were added to a solution of aniline (1 eq) and 5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxylic acid (1.2 eq) in ethyl acetate (0.25M) from general step 3. The resulting reaction mixture was heated to reflux for 2h. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic extracts were mixed and dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel using a mixture of ethyl acetate and n-hexane as eluent to obtain the title product.

General step 6-silylation reaction of azaalcohols

An aliquot of imidazole (2.5 eq) was added to a solution of 4-aza Zhuo Chun 5 (1 eq) in dichloromethane (0.16M) at room temperature. Tert-butyl (chloro) diphenylsilane (1.35 eq) was then added and the resulting reaction mixture was stirred at room temperature for 1h. The reaction mixture was diluted with water (50 ml) and extracted with dichloromethane (×3). The organic extracts were combined, washed with water and brine, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. The resulting crude product was purified by silica gel chromatography using a mixture of ethyl acetate and n-hexane as an eluent to obtain the title product 7.

General procedure 7-acylation of Azaalcohol scaffolds (Azapanol Scaffold) (examples 47-49)

(a) Pyridine (10 eq) and phosphorus oxychloride (7.2 eq) were added to a solution of 5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxylic acid (1 eq) in dichloromethane (3 mL) under nitrogen at 0 ℃. Aniline (6)A solution of (1.33 eq.) in dichloromethane (0.26M) was added to the mixture and the resulting reaction mixture was stirred at room temperature for 1h. The reaction mixture was acidified with dilute hydrochloric acid solution and extracted with dichloromethane (×3). The organic extracts were combined, washed with water and brine, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel using a mixture of ethyl acetate and n-hexane as eluent to obtain the title product.

(b) In a sealed vial, methanol (54 eq) and acetyl chloride (0.34 eq) were stirred for 20min under nitrogen at 0deg.C, and then the resulting mixture was added dropwise to a stirred solution of amide (1 eq) in methanol (0.15M) at 0deg.C. The resulting reaction mixture was heated at 80℃for 1h. After cooling to room temperature, the reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate (×3). The organic extracts were combined, washed with water and brine, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. The resulting crude product was purified by preparative HPLC using 10mM aqueous ammonium bicarbonate and acetonitrile as mobile phases.

General procedure 8-Synthesis of azaalcohol-supporting 5- (4-pyridyl) furan analogs (examples 44-46)

(b) Bromide (1 equivalent), pyridine-4-boronic acid (1.2 equivalent), pdCl were reacted under nitrogen ₂ (PPh ₃ ) ₂ (0.05 eq.) 1, 2-Dimethoxyethane (0.08M) in 2M aqueous sodium carbonate (2 eq.) under reflux with heating7h. The reaction mixture was cooled to room temperature and excess DME was removed under reduced pressure. The pH of the residue was adjusted to pH 1 with 2M aqueous hydrochloric acid. The solution was extracted with dichloromethane (×3). The dichloromethane extract was discarded. The remaining aqueous solution was neutralized to pH-9 with solid sodium bicarbonate and extracted with ethyl acetate (×3). The organic extracts were combined, washed with water and brine, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel using a mixture of ethyl acetate and n-hexane as eluent to obtain the title product.

(c) In a sealed vial, methanol (54 eq) and acetyl chloride (0.34 eq) were stirred for 20min under nitrogen at 0deg.C, and then the resulting mixture was added dropwise to a stirred solution of amide (1 eq) in methanol (0.15M) at 0deg.C. The resulting reaction mixture was heated at 80℃for 1h. After cooling to room temperature, the reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate (×3). The organic extracts were combined, washed with water and brine, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. The resulting crude product was purified by preparative HPLC on 10mM aqueous ammonium bicarbonate and acetonitrile.

General procedure 9-Synthesis of primitive amide precursor

A solution of acid 2 (1 eq.) and thionyl chloride (1.5 eq.) in chloroform (0.18M) was heated to reflux for 1h. After concentration under reduced pressure, the resulting residue was dissolved in THF and the reaction mixture was purged with ammonia at room temperature for 2h. The resulting reaction mixture was quenched with water and extracted with ethyl acetate (×3). The organic extracts were mixed and washed with brine, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure and the resulting crude product was purified by flash chromatography on silica gel using n-hexane containing 80% ethyl acetate as eluent.

General procedure 10-Synthesis of N-methylamide precursor

N, N-diisopropylamine (3.1 eq) and HATU (1.5 eq) were added to acid (2) (1 eq) under nitrogen at 0deg.C) In DMF (0.3M) and stirred for 15min. A solution of methylamine in THF (2 m,1.2 eq) was added to the reaction mixture and the mixture was stirred for 2h. The resulting reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic extracts were mixed and washed with brine, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel using n-hexane containing 30% ethyl acetate as eluent.

General procedure 11-Synthesis of N, N-dimethylamide precursors

N, N-diisopropylamine (3.1 eq) and HATU (1.5 eq) were added to a solution of acid (2) (1 eq) in DMF (0.3M) under nitrogen at 0℃and stirred for 15min. A solution of methylamine in THF (2 m,1.2 eq) was added to the reaction mixture and the mixture was stirred for 2h. The resulting reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic extracts were mixed and washed with brine, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure to provide the material of sufficient purity for the next step.

General procedure 12-Synthesis examples 72-77, 84-90

A2.0M solution of trimethylaluminum in toluene (3 eq.) was added dropwise to a solution of aniline (9 or 10 or 11) (1 eq.) in methylene chloride (0.075M) in a nitrogen atmosphere at 0deg.C. The mixture was stirred at room temperature for 1H, then a solution of methyl 5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxylate or methyl 5- (4-pyridinyl) furan-2-carboxylate (1 eq) in dichloromethane (0.15M) was added dropwise under nitrogen at room temperature. The resulting reaction mixture was stirred at room temperature for 16h, then diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane (×3). The organic extracts were mixed, washed with brine and dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure and the resulting crude product was purified by flash chromatography on silica gel using chloroform containing 2% methanol as eluent.

General step 13-Synthesis of piperazine-substituted aminomethyl precursors

(a) N, N-Diisopropylethylamine (1.7 eq) and formyl chloride (1.1 eq) were added to piperidine 2 (z=co ₂ H) (1 eq.) in dichloromethane (1M) and the resulting reaction mixture was stirred at room temperature overnight. After quenching with saturated ammonium bicarbonate solution, the aqueous solution was extracted with ethyl acetate (×3). The organic extracts were mixed, washed with 5% citric acid solution, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure to provide the material of sufficient purity for the next step.

(b) Sodium azide (5 eq.) was added to a solution of formyl derivative (4) (1 eq.) in DMF (0.34M) and the resulting mixture was heated at 110 ℃ for 16h. After cooling, the resulting reaction mixture was quenched with cold water and extracted with ethyl acetate (×3). The organic extracts were combined, washed with cold brine (×2), then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure to provide azide of sufficient purity for the next step.

(c) Triphenylphosphine (1 eq) was added to a solution of azide (1 eq) in dry methanol (1.1M) and the resulting reaction mixture was heated to reflux for 15min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, diluted with cold water (100 mL), and the resulting aqueous solution was extracted with ethyl acetate (×3). The organic extracts were combined, washed with cold brine (×2), then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel using chloroform containing 5% methanol as eluent to give amine 12.

General procedure 14-Boc protection of amines

Boc anhydride (1.2 eq.) and triethylamine (1.5 eq.) were added to a solution of amine 12 (1 eq.) in THF (0.39M) under nitrogen at room temperature and the resulting reaction mixture was stirred at room temperature for 2h. The reaction mixture was quenched with water and extracted with ethyl acetate (×3). The organic extracts were combined, washed with brine (×2), then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure and then flash chromatography on silica gel using n-hexane containing 10% ethyl acetate as eluentThe crude product obtained was purified.

General step 15-Synthesis of benzyl-protected methylamines

(a) A solution of aniline 12 (1 equivalent) and benzaldehyde (1 equivalent) in methanol (0.24M) was stirred for 30min at room temperature under nitrogen, and then sodium triacetoxyborohydride (2 equivalent) was added to the reaction mixture in proportion at 0 ℃. After stirring at room temperature for 16h, the reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate (×3). The organic extracts were mixed and washed with brine, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel using n-hexane containing 35% ethyl acetate as eluent.

(b) A solution of benzylamine (1 eq.) in formalin (37-41% w/v aqueous formaldehyde) (10 eq.) in methanol (0.14M) was stirred for 30min at room temperature under nitrogen. Sodium triacetoxyborohydride (2 eq.) was then added to the reaction mixture in proportions at 0 ℃. The resulting reaction mixture was stirred at room temperature for 1h. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate (×3). The organic extracts were mixed and washed with brine, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel using n-hexane containing 35% ethyl acetate as eluent.

General step 16-reductive amination method for synthesizing dimethylaminomethylpiperazine precursor

A solution of benzylamine (1 eq.) in formalin (37-41% w/v aqueous formaldehyde) (10 eq.) in methanol (0.14M) was stirred for 30min at room temperature under nitrogen. Sodium triacetoxyborohydride (2 eq.) was then added to the reaction mixture in proportions at 0 ℃. The resulting reaction mixture was stirred at room temperature for 1h. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate (×3). The organic extracts were mixed and washed with brine, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. N-hexane containing 35% ethyl acetate was used as the solventThe crude product was purified by column chromatography on silica gel.

General procedure 17-Synthesis example 81

(a) Pyridine (10 eq) and phosphorus oxychloride (7.2 eq) were added to a solution of 5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxylic acid (1 eq) in dichloromethane (0.18M) under nitrogen at 0 ℃. A solution of aniline (1.33 eq) in dichloromethane (0.11M) was added to the mixture and the resulting reaction mixture was stirred at room temperature for 1h. Slowly pouring the reaction mixture into ice-cold water; basified to pH 8 with saturated ammonium bicarbonate solution (50 mL) and extracted with dichloromethane (. Times.3). The organic extracts were mixed, washed with saturated potassium hydrogen sulfate solution and brine (×2), and then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure and the resulting crude product was purified by flash chromatography on silica gel using n-hexane containing 20% ethyl acetate as eluent.

(b) 4N HCl in dioxane (10 eq.) was added dropwise to a solution of amide (0.22 g,0.38 mmol) in dioxane (0.19M) under nitrogen at 0deg.C and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was neutralized to pH 9 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (. Times.4). The organic extracts were mixed and washed with saturated aqueous sodium bicarbonate solution, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. The resulting crude product was purified by preparative HPLC using 10mM aqueous ammonium bicarbonate and acetonitrile as mobile phases to yield the title compound.

General procedure 18-Synthesis example 78

(a) Pyridine (1.02 g,12.90 mmol) and phosphorus oxychloride (1.39 g,9.03 mmol) were added to a solution of 5-bromofuran-2-carboxylic acid (9) (0.246 g,1.29 mmol) in dichloromethane (7 mL) under nitrogen at 0deg.C. A solution of aniline (8) (0.5 g,1.29 mmol) in methylene chloride (8 mL) was then added to the reaction mixture, and the resulting reaction mixture was stirred at room temperature for 15min. Slowly pouring the reaction mixture into ice-cold water; basified to pH 8 with saturated ammonium bicarbonate solution (50 mL) and extracted with dichloromethane (. Times.3). Mixing the organic extracts with saturated potassium bisulfateThe solution was washed with brine (×2) then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure and the resulting crude product was purified by flash chromatography on silica gel using n-hexane containing 8% ethyl acetate as eluent.

(b) Bromide (1 equivalent), pyridine-4-boronic acid (1.2 equivalent), pdCl were reacted under nitrogen ₂ (PPh ₃ ) ₂ (0.05 eq.) a solution of 1, 2-dimethoxyethane (0.08M) in 2M aqueous sodium carbonate (2 eq.) was heated to reflux for 17h. The reaction mixture was cooled to room temperature and excess DME was removed under reduced pressure. The pH of the residue was adjusted to pH 1 with 2M aqueous hydrochloric acid. The solution was extracted with dichloromethane (×3). The dichloromethane extract was discarded. The remaining aqueous solution was neutralized to pH-9 with solid sodium bicarbonate and extracted with ethyl acetate (×3). The organic extracts were combined, washed with water and brine, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel using a mixture of ethyl acetate and n-hexane as eluent to obtain the title product.

(c) 4N HCl in dioxane (10 eq.) was added dropwise to a solution of amide (0.22 g,0.38 mmol) in dioxane (0.19M) under nitrogen at 0deg.C and the reaction mixture stirred at room temperature for 2h. The reaction mixture was neutralized to pH 9 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (. Times.4). The organic extracts were mixed and washed with saturated aqueous sodium bicarbonate solution, then dried over anhydrous Na ₂ SO ₄ Drying. The solvent was removed under reduced pressure. The resulting crude product was purified by preparative HPLC using 10mM aqueous ammonium bicarbonate and acetonitrile as mobile phases to yield the title compound.

General procedure 19-benzylamine hydrogenolysis reaction-Synthesis examples 79 and 82

A solution of benzyl derivative (11) (1 equivalent) in methanol (1M) was added to a methanol (1M) slurry of Rosenmund catalyst (20% w/w) under nitrogen. The resulting reaction mixture was stirred under hydrogen at room temperature for 6h. The resulting reaction solution was filtered through a small pad of celite and washed with methanol. The solvent was removed under reduced pressure and the resulting crude product was purified by preparative HPLC using 10mM aqueous ammonium bicarbonate and acetonitrile as mobile phases.

Analytical data for all compounds are shown in table 2.

Compounds in tables 2 and 3 having a stereocenter in the pyrrolidine or azepane ring were synthesized and tested as racemic mixtures of the R enantiomer and the S enantiomer, unless otherwise indicated.

In vitro SRPK1 assays

As previously described, in WO2017/064512A1, inhibition of SRPK1 by candidate compounds was detected using a Kinase-Glo assay.

CYP inhibition assay

Summary of procedure:

table 1: CYP inhibition protocol

The detection step comprises:

158 μl of human liver microsome assay stock solution was added to the reaction plate (0.253 mg/mL,158 μl/well). Then 2 μl of test compound/positive inhibitor test solution was added to the reaction plate (2 μl/well). For control, 2 μl of Acetonitrile (ACN) containing DMSO (without inhibitor) was added to the reaction plate. mu.L of matrix pool (substrate pool) was added to all wells of the reaction plate. The samples were mixed in a vortexing apparatus and pre-incubated at 37℃for 20min. The NADPH solution was preheated at 37℃for 5min. mu.L of the preheated NADPH solution was added to the reaction plate, followed by incubation at 37℃for 10min. Cold ACN (200. Mu.L/well) was added to the reaction mixture and centrifuged at 4000rpm for 20min to terminate the reaction. After centrifugation, the supernatant was separated and analyzed by LC-MS/MS.

Calculation of inhibition using Graphpad Prism softwarePercent of System and IC ₅₀ 。

The results of the SRPK1 assay and the CYP inhibition assay are shown in table 3.

As control compounds, the following compounds were tested:

control example 1: n- (2- (4- (pyridin-2-ylmethyl) -piperazin-1-yl) -5-trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

control example 2: n- (2- (4- (furan-2-ylmethyl) piperazin-1-yl) -5- (trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide;

control example 3: n- (2- (4- ((1H-pyrazol-3-yl) methyl) piperazin-1-yl) -5- (trifluoromethyl) -phenyl) -5- (tetrahydro-2H-pyran-4-yl) furan-2-carboxamide;

control example 4: n- (2- (4- (oxazol-4-ylmethyl) piperazin-1-yl) -5- (trifluoromethyl) phenyl) -5- (pyridin-4-yl) furan-2-carboxamide; and

control example 5:5- (pyridin-4-yl) -N- (2- (5- (thiazol-2-ylmethyl) piperazin-1-yl) -5- (trifluoromethyl) phenyl) furan-2-carboxamide.

It follows that, unlike the control compounds, all compounds of the invention are not only potent inhibitors of SRPK1, but also exhibit acceptable levels of CYP inhibition. With acceptable levels of CYP inhibition, it is generally believed that the less potent the candidate compound is at inhibiting any CYP enzyme, the less the risk of adverse drug-drug interactions or other side effects associated with toxicity. In addition, acceptable levels of CYP activity can be measured using a function of the SRPK1 activity of a particular compound. In particular, CYP inhibitors are less potent than SRPK1 inhibitors and are at least 100-fold less potent in this regard (according to IC ₅₀ Measurement value determination) are also considered advantageous compounds, which represent a clinically significant improvement over prior art compounds.

More generally, if the drug candidate compound is IC for any core CYP enzyme associated with drug metabolism (CYP 1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3 A4) ₅₀ Above 1 μm (1000 nM), then the risk of any adverse drug-drug interactions or other toxicity problems is considered to be acceptably lowTo a degree of (3). For any CYP tested, it is especially preferred that the CYP activity profile is greater than 10. Mu.M (10000 nM).

While these core CYPs are responsible for metabolizing more than 95% of drugs and other exogenous substances, CYP2D6 and CYP3A4 are considered to be the most important in this core group. Thus, even mild inhibitors of these two enzymes are not considered suitable candidates for systemic administration.

Notably, for topical administration, such as topical treatment of ocular neovascularization, less attention is paid to CYP activity, as topically administered compounds (e.g., to the eye) are less likely to be metabolized in the liver, with CYP activity occurring primarily in the liver.

In vivo angiogenesis detection: laser-induced Choroidal Neovascularization (CNV) protocol

Female C57/B6 mice of 6 to 8 weeks of age were anesthetized by intraperitoneal injection from a mixture of 50mg/kg ketamine and 0.5mg/kg medetomidine. The pupil is dilated immediately by topical application (eye drops) of a dilater such as 5% phenylephrine hydrochloride and 1% topiramate. Four photocoagulation lesions were created between the "larger" retinal blood vessels in the clear space using a green Merilas 532 a laser (450 mw,130 ms) with no blood vessels in the peripapillary distribution spaced at 1-2 disc diameter intervals in each eye. Only clear laser lesions with subretinal bubbles at the time of treatment were included in the study. Immediately after laser photocoagulation, eye drops of the candidate compound were topically administered to the animals twice daily (10 μl of 2mg/mL eye drops, held in the eyes for 30 seconds to prevent the animals from wiping off the eye drops).

After one week, mice were anesthetized by intraperitoneal injection with a mixture of 50mg/kg ketamine and 0.5mg/kg medetomidine. The pupil is dilated immediately by topical application (eye drops) of a dilater such as 5% phenylephrine hydrochloride and 1% topiramate. The mice were dosed with sodium fluorescein (10%) by intraperitoneal injection. Phase difference pictures and green fluorescence fundus pictures were obtained by an angiogram microscope and a camera focusing each lesion. Mice were sacrificed by the method of protocol 1 and eyes were not fixed for dissecting retina and extracting proteins, or eyes were fixed and nuclei were removed for choroidal staining and examination.

The optical density of each well was measured immediately using a microplate reader set at 450 nm.

Fig. 1 (a) shows that compound 12 increased anti-angiogenic activity against lesion size in the laser-induced mouse CNV model and the same efficacy as the control compound, based on the optical image as shown in fig. 1 (b).

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Table 2: analysis data

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Table 3: SRPK1 and CYP Activity assay data

Although the compounds and related aspects have been described with reference to certain examples, those skilled in the art will appreciate that various modifications, changes, omissions, and substitutions can be made without departing from the spirit of the invention. Accordingly, the compounds and related aspects of the invention are limited only by the scope of the following claims. That is, it is to be understood that the protection provided by the following claims is not limited to literally scope, but extends to equivalent compounds or variant compounds and related aspects where equivalents or variants are apparent to achieve the same technical result in the same manner, e.g., substitution of a bromo substituent for a chloro substituent, without significant difference in biological activity.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, which is a compound of formula (I)

Or one of the following compounds:

Wherein, for the compound of formula (I):

n=1, 2 or 3;

R ₂ is furyl having a 4-tetrahydropyranyl or 4-pyridyl substituent, or 2-pyridyl;

R ₃ is hydroxy groupHydroxymethyl, methoxy, C ₁ -C ₃ Alkyl, carboxyl, -C (O) NR ₅ R ₆ Or CH (CH) ₂ NR ₅ R ₆ ；

R ₃ And R is ₄ Together with the carbon atoms adjacent thereto form a 3-to 6-membered carbocyclic ring or a 3-to 6-membered heterocyclic ring; and is also provided with

R ₅ And R is ₆ Are linked together to form a 5-or 6-membered nitrogen-containing heterocycle.

2. The compound of claim 1, wherein:

n=1, 2 or 3;

R ₂ is furyl having a 4-tetrahydropyranyl or 4-pyridyl substituent;

3. The compound of claim 1, wherein:

n＝1；

4. The compound of claim 1, wherein:

n＝2；

R ₃ is hydroxy, hydroxymethyl, methoxy, C ₁ -C ₃ Alkyl, carboxyl, -C (O) NR ₅ R ₆ Or CH (CH) ₂ NR ₅ R ₆ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

R ₅ And R is ₆ Are linked together to form a 5-or 6-membered nitrogen-containing heterocycle。

5. The compound of claim 1, wherein:

n＝3；

R ₂ is furyl having a 4-tetrahydropyranyl or 4-pyridyl substituent;

6. The compound of claim 1, wherein R ₂ Is a 4-tetrahydropyranyl substituted furanyl group.

7. The compound of claim 1, wherein:

n=1, 2 or 3;

R ₂ is a 2-pyridyl group;

8. The compound of claim 1, wherein:

R ₃ is hydroxy, hydroxymethyl, methoxy, methyl, carboxy, -C (O) NR ₅ R ₆ Or CH (CH) ₂ NR ₅ R ₆ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

9. The compound of claim 1, wherein:

R ₃ is a hydroxyl group; and

R ₄ is methyl, ethyl, cyclopropyl, phenyl, benzyl or cyclopropylmethyl.

10. The compound of claim 1, wherein:

R ₃ is-C (O) NR ₅ R ₆ Or CH (CH) ₂ NR ₅ R ₆ ；

R ₄ Is methyl; and

R ₅ good R ₆ Independently selected from hydrogen and methyl; or alternatively

11. The compound of claim 1, wherein:

R ₃ And R is ₄ Together with the carbon atoms adjacent thereto form a 3-to 6-membered carbocyclic ring or a 3-to 6-membered heterocyclic ring.

12. The compound of claim 1, wherein the carbocycle or heterocycle is a 5-or 6-membered saturated carbocycle or heterocycle.

13. The compound of claim 1, wherein:

n=1 or 3; and is also provided with

Wherein the compound is enantiomerically pure.

14. The compound of claim 1, wherein:

n=1 or 3;

R ₃ is hydroxy, -C (O) NR ₅ R ₆ Or CH (CH) ₂ NR ₅ R ₆ ；

R ₄ Is hydrogen or methyl;

R ₅ And R is ₆ Are linked together to form a 5-or 6-membered nitrogen-containing heterocycle; and is also provided with

Wherein the compound is the R enantiomer.

15. The compound of claim 1, wherein:

n=1 or 3;

R ₃ is hydroxy, -C (O) NR ₅ R ₆ Or CH (CH) ₂ NR ₅ R ₆ ；

R ₄ Is hydrogen or methyl;

Wherein the compound is the S enantiomer.

16. The compound of claim 1, wherein:

R ₁ is chloro, trifluoromethyl or cyclopropyl.

17. The compound of claim 1, wherein R ₃ is-C (O) NR ₅ R ₆ Or CH (CH) ₂ NR ₅ R ₆ The method comprises the steps of carrying out a first treatment on the surface of the And R is ₅ And R is ₆ Are linked together to form a 5-or 6-membered nitrogen-containing heterocycle; and is also provided with

Wherein the nitrogen-containing heterocycle is a pyrrolidine, piperidine or morpholine heterocycle.

18. A pharmaceutical composition comprising a compound of claim 1.

19. The pharmaceutical composition of claim 18, further comprising one or more additional active ingredients and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition suitable for intraocular injection comprising a compound of claim 1.

21. The pharmaceutical composition of claim 20, further comprising one or more additional active ingredients and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition suitable for topical administration to the eye comprising a compound of claim 1.

23. The pharmaceutical composition of claim 22, further comprising one or more additional active ingredients and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition suitable for systemic administration comprising a compound of claim 1.

25. The pharmaceutical composition of claim 24, further comprising one or more additional active ingredients and a pharmaceutically acceptable carrier.

26. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of ocular neovascularization.

27. The use of claim 26, wherein the treatment or prevention of ocular neovascularization comprises treatment or prevention of age-related macular degeneration or macular edema.

28. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for anti-angiogenic therapy in a mammalian subject.

29. The use of claim 28, wherein the anti-angiogenic therapy for a mammalian subject is a cancer therapy in a mammalian subject.

30. The use of a compound as claimed in claim 1 for the preparation of a medicament for the treatment or prophylaxis of microvascular hyperpermeability disorders, or for the modulation of VEGF _xxx An agent that has pro-angiogenic pro-permeability properties of the same type, or supports epithelial cell survival without increasing permeability, or reduces the characteristics of the fenestration of the epithelial filter.

31. The use of claim 30, wherein the epithelial filter membrane aperture characteristic is number density and/or size.

32. The use of a compound according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of neurological and neurodegenerative disorders, or as neuroprotective or neuroregenerative agent in vivo or in vitro.

33. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of pain.

34. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of fibrosis in a mammalian subject.

35. The use of claim 34, wherein the treatment or prevention of fibrosis in a mammalian subject is prevention of idiopathic pulmonary fibrosis in a mammalian subject.